Polyphenolic compounds exhibit significant antioxidant and anti-inflammatory activities, scavenging excess free radicals and reducing cellular damage caused by oxidative stress (12). By boosting intracellular antioxidant enzyme levels and directly scavenging reactive oxygen species (ROS), polyphenols protect DNA from oxidative damage, thereby reducing the risk of mutation and carcinogenesis. Additionally, polyphenols can inhibit signaling pathways associated with chronic inflammation, such as nuclear factor-κB (NF-κB), thereby decreasing the production of pro-inflammatory mediators. Studies have shown that polyphenols, such as curcumin, can block NF-κB activation and downregulate the expression of pro-inflammatory genes, including interleukin-6 and cyclooxygenase-2 (13). By reducing the levels of these pro-tumor inflammatory factors, polyphenols lessen the constant irritation caused by inflammation on tissues, thereby helping to reduce the risk of cancer development and progression.

Polyphenols induce programmed cell death in cancer cells, mainly via mitochondria-mediated endogenous pathways. They tend to upregulate the pro-apoptotic protein Bax and inhibit the anti-apoptotic protein Bcl-2, altering the Bax/Bcl-2 ratio to promote the release of cytochrome c, which in turn activates downstream apoptosis-executing proteins such as caspase-3 and caspase-9 (14, 15). Curcumin has been shown to downregulate Bcl-2 family proteins by inhibiting pathways such as NF-κB, triggering the cysteine asparaginase cascade in cancer cells to trigger apoptosis (12). Polyphenols such as resveratrol likewise enhance apoptotic signaling, making cancer cells more susceptible to apoptosis. In addition to inducing apoptosis, polyphenols also affect the regulation of autophagy, a cellular survival/death process. Many polyphenols initiate the autophagy program by inhibiting the PI3K/Akt/mTOR signaling pathway or activating energy-sensing pathways such as AMPK (16). This implies that polyphenols can disrupt the inhibition of autophagy by mTOR and induce autophagic cell death or autophagy-mediated survival stress relief in cancer cells. Experimental evidence showed that resveratrol treatment upregulated the expression of the autophagy marker protein Beclin-1 and increased the LC3-II/LC3-I ratio, demonstrating that it induced autophagy in cancer cells while also promoting apoptosis (14).

Polyphenols also exert anticancer effects by remodeling the tumor microenvironment. They can intervene in the function of peritumoral support cells, thereby weakening the tumor's growth environment. Studies have shown that resveratrol treatment reduces the proportion of tumor-promoting M2 tumor-associated macrophages (TAM) in tumor tissues and significantly enhances the activation of tumor-infiltrating CD8+ T cells (17). In addition, resveratrol can effectively eliminate senescent cancer-associated fibroblasts (CAF) in tumor tissues and diminish the supportive effect of CAF on tumor cell proliferation and invasion, thus inhibiting the progression of pancreatic cancer (18). In terms of tumor angiogenesis, polyphenols inhibit neovascularization by blocking pro-angiogenic signals. Specific mechanisms include downregulation of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) expression (15). Taking tea polyphenol epigallocatechin gallate (EGCG) as an example, it can significantly reduce the levels of VEGF-A and HIF-1α secreted by tumor cells and inhibit tumor angiogenesis and nutrient supply, thus effectively hindering tumor growth and metastasis (15).

Polyphenols exert multitargeted anticancer effects through modulation of key signaling pathways. The green tea catechin EGCG can inhibit multiple pro-tumor signaling cascades. It has been shown to reduce the activation of the MAPK/ERK and PI3K/Akt pathways, upregulate the cyclin-dependent kinase inhibitor p21, and trigger mitochondrial apoptosis by downregulating the anti-apoptotic proteins Bcl-2/Bcl-xL (19–21). EGCG also attenuates cancer cell invasion and metastasis by lowering matrix metalloproteinases (MMPs) and suppressing angiogenic factors (22). Another well-studied polyphenol, quercetin, induces apoptosis via the PI3K/Akt/mTOR axis. In hepatocellular carcinoma cells, quercetin treatment downregulated proline 4-hydroxylase (P4HA2) and inhibited the PI3K/Akt/mTOR signaling pathway, leading to pronounced apoptosis (23). This highlights how polyphenols can interfere with survival pathways and activate intrinsic death programs.

Curcumin emerges as a potent miRNA modulator with specific targeting of oncogenic and tumor suppressor miRNAs. Recent studies demonstrate that curcumin significantly downregulates miR-21 (oncomiR suppression) while upregulating miR-34a/b/c by two- to four-fold in colorectal cancer cells (24). The compound activates tumor suppressor miRNAs through ROS/NRF2 pathway activation, independent of p53 status, and modulates miRNA promoters through direct transcription factor binding (24). Clinical evidence from 2023 shows that a curcumin nanomicelle formulation significantly reduces miR-155 (p = 0.002), miR-138 (p = 0.024), and miR-16 (p = 0.0001) in human subjects, demonstrating systemic miRNA modulation (25). In colorectal cancer models, curcumin treatment reduced IC50 values from 40 ± 4.2 μM to 5 ± 0.36 μM when combined with 5-FU, with miR-34a expression increasing 2.5-fold in HCT-116 cells (24).

Resveratrol targets the miR-200 family and miR-125b-5p for epithelial–mesenchymal transition (EMT) inhibition. The compound upregulates miR-200c-3p and miR-125b-5p by two- or three-fold, suppressing mesenchymal markers and inducing apoptosis through the modulation of the Bcl-2/Bax ratio modulation (26). A breakthrough 2022 study using genetically engineered mice showed that resveratrol prevents 60% of tumors and achieves 33% complete remission through miR-96 upregulation, which inhibits KRAS translation (27). EGCG demonstrates unique miRNA targeting through HIF-1α stabilization. The compound binds directly to HIF-1α (Kd = 3.47 μM), upregulating miR-210 and enhancing miR-155-5p expression by 2.12 ± 0.02-fold in HCT-116 cells (28). This miRNA modulation reverses chemoresistance by targeting MDR1, reducing the 5-FU IC50 from 150 ± 6.4 μM to 11 ± 0.96 μM in DLD1 cells (29). Quercetin affects 105 miRNAs in pancreatic cancer (80 upregulated, 25 downregulated), with particular emphasis on the downregulation of miR-200b-3p, which reduces cancer stem cell aggressiveness. The compound targets Notch signaling through miRNA-mediated regulation of the Notch/Numbl pathway, while miR-217 upregulation reduces cisplatin resistance in ovarian cancer models (30) (Figure 3).

Carotenoids are a class of strong antioxidants that scavenge free radicals and reduce DNA damage from oxidative stress, thereby preventing genetic mutations and cancerous lesions (31, 32). However, under certain conditions (e.g., high oxygen partial pressure, high doses, or environments with high levels of ROS already present in tumor cells), carotenoids can be converted from antioxidants to pro-oxidants, generating excess ROS and triggering oxidative stress that induces cancer cell death (32). This “dual” effect allows carotenoids to play a protective role in normal cells while triggering apoptosis in cancer cells by increasing their ROS levels, resulting in a selective killing effect on tumors. In other words, carotenoids optimize the redox balance of normal cells while enhancing oxidative stress in tumor cells, thus inhibiting tumor growth (32).

Carotenoids also exert anticancer effects through immunomodulation. Studies have shown that these compounds can affect the function of various immune cells, such as enhancing the activity of T lymphocytes and natural killer cells (NK cells), and regulating macrophage function, thereby enhancing the overall antitumor immune response of the body (31, 33). In addition, carotenoids have significant anti-inflammatory effects, inhibiting chronic inflammatory responses in the tumor microenvironment. Lycopene downregulates the production of pro-inflammatory cytokines and decreases the expression of inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and COX-2, through the inhibition of the NF-κB signaling pathway (34, 35). This inhibition of pro-inflammatory signaling helps to weaken the pro-growth inflammatory environment of tumors, reduces the opportunities for tumor cells to evade immune surveillance through inflammation, and enhances the effectiveness of the antitumor immune response. As a result, carotenoids synergistically inhibit tumor development by creating a microenvironment more conducive to the immune system's recognition and elimination of cancer cells (36).

Carotenoids also inhibit tumor growth by regulating the cell cycle and promoting DNA damage repair. Many studies have found that carotenoids can affect the expression of cell cycle-related proteins, such as increasing the levels of the cell cycle inhibitors p21Cip1 and p27Kip1, while inhibiting the activity of Cyclin and its related kinases, thereby inducing cell cycle arrest in cancer cells (37, 38). β-Carotene treatment arrests a variety of cancer cells in the G0/G1 or G2/M phase: On the one hand, it upregulates CDK inhibitors such as p21 and decreases Cyclin A levels, and on the other hand, it increases intracellular p27Kip1 levels by inhibiting the expression of Skp2 (the protein that drives p27 degradation). Both pathways effectively prevent the continued proliferation of cancer cells (39–41).

In addition to inhibiting proliferation, carotenoids affect the cellular DNA damage response pathway, enhancing p53-mediated gene monitoring and repair. Activated p53 triggers cell cycle arrest to provide damaged DNA with enough time to repair or, in the case of excessive damage, to initiate apoptosis, thus preventing the proliferation of cells carrying severe genetic defects (42, 43). Certain carotenoids can upregulate p53 and its downstream repair genes to improve DNA repair efficiency. For example, fucoxanthin was found to induce a G0/G1 phase block in cancer cells while upregulating GADD45α, a DNA repair gene regulated by p53, which helps maintain genomic stability and reduce cancer risk (44). Through these mechanisms, carotenoids can reduce the accumulation of DNA damage and the occurrence of gene mutations, playing an anticancer role at the molecular level.

Carotenoids likewise impact critical molecular pathways in cancer cells. Lycopene, a carotenoid found in tomatoes, is known to suppress chronic inflammatory signaling; notably, it inhibits NF-κB activation, thereby reducing pro-inflammatory cytokines and mediators such as COX-2 and iNOS in the tumor microenvironment. This attenuation of NF-κB leads to decreased tumor-promoting inflammation and can impair angiogenesis signals, hindering tumor growth. Lutein, another dietary carotenoid, directly influences cell survival pathways. In lung cancer models, lutein was found to induce apoptosis by modulating PI3K/Akt signaling, effectively inhibiting Akt to trigger cancer cell death while sparing normal cells (45). Moreover, lutein can act as a pro-oxidant under tumor conditions: in gastric cancer cells, lutein elevated intracellular ROS via NADPH oxidase, which unexpectedly led to NF-κB–mediated upregulation of pro-apoptotic factors and caspase-3 activation, culminating in apoptosis (46). These examples illustrate that carotenoids can both protect normal cells and selectively kill cancer cells by shifting redox and signaling balances toward cell cycle arrest and apoptosis.

Lycopene modulates oxidative stress-responsive miRNAs in prostate cancer through antioxidant pathways. Clinical studies demonstrate that circulating lycopene increases with supplementation (pooled mean difference: 0.1361; 95% CI [0.0574; 0.2148]), correlating with a 7% reduction in specific prostate cancer types. The compound induces apoptosis and cell cycle arrest through miRNA-mediated regulation of apoptotic proteins at effective concentrations of 5–25 μM (47). β-Carotene affects cancer pathways through Pin1 inhibition and PI3K/AKT signaling suppression; however, clinical studies reveal an increased lung cancer risk in smokers (RR: 1.19; 95% CI: 1.08–1.32), emphasizing the importance of personalized approaches based on individual risk factors (48).

In terms of clinical translation, carotenoids are being investigated for cancer prevention and adjuvant therapy. Epidemiologic studies have shown that high fruit and vegetable intake is associated with a reduced risk of certain cancers, but high doses of carotenoid supplements may be counterproductive in specific populations (31). Therefore, one of the current research priorities is to clarify the optimal dosage of different carotenoids and the applicable populations to safely and effectively exert their anticancer preventive effects. Meanwhile, the potential of carotenoids as chemotherapeutic adjuvants has also received attention. It has been proposed to combine carotenoids with certain chemotherapeutic drugs: carotenoids play an antioxidant protective role in normal tissues to alleviate the side effects of chemotherapy while exhibiting pro-oxidant effects in tumor tissues to enhance the killing of cancer cells (49). These recent advances suggest that the rational utilization of the multiple mechanisms of antioxidant and immune enhancement of carotenoids is expected to improve the efficacy of cancer prevention and treatment, but more clinical trials are needed to validate their safety and efficacy.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce the levels of pro-inflammatory cytokines and downregulate inflammatory mediators such as COX-2, TNF-α, NF-κB, and prostaglandin E2 (PGE₂), which attenuates cancer-related inflammatory responses (50, 51). Meanwhile, DHA and EPA exhibit anticancer effects by inducing apoptosis and inhibiting proliferation and angiogenesis. Omega-3 polyunsaturated fatty acids have significant anti-inflammatory effects and may reduce the inflammatory response in the tumor microenvironment through several mechanisms. EPA and DHA can competitively replace arachidonic acid in the cyclooxygenase pathway, reducing the synthesis of pro-inflammatory mediators such as PGE₂ and leukotrienes (52). In addition, omega-3-derived bioactive products promote inflammation resolution and help to end chronic inflammation (53). At the level of signaling pathways, omega-3 inhibits the activation of the pro-inflammatory transcription factor NF-κB and prevents its translocation into the nucleus, thereby downregulating the expression of a series of pro-inflammatory genes. Cellular experiments have shown that EPA treatment blocked the entry of NF-κB p65 into the nucleus and reduced its activity (51). Meanwhile, DHA reduces the expression level of the COX-2 enzyme in cancer cells and decreases oncogenic inflammatory signaling mediated by COX-2 (54).

Together, these effects reduce tumor-associated pro-inflammatory cytokine release and inflammatory cascade responses, thereby helping to inhibit inflammation-driven tumor progression. Clinical studies also support the anti-inflammatory benefits of omega-3. Omega-3 supplementation in cancer patients reduces inflammatory markers such as IL-6 and C-reactive protein (CRP) and improves inflammation-based prognostic scores (55). In conclusion, omega-3 fatty acids alleviate cancer-associated chronic inflammation and facilitate antitumor therapy by inhibiting NF-κB and reducing COX-2 and pro-inflammatory mediator production.

Omega-3 fatty acids can be incorporated into the phospholipid bilayer of cell membranes, significantly altering the fatty acid composition and biophysical properties of the membranes. This incorporation decreases the proportion of ω-6 fatty acids, such as arachidonic acid, and increases the content of ω-3 fatty acids, thereby improving membrane fluidity and flexibility (56). Changes in membrane structure affect the composition and stability of membrane microdomains, which in turn regulate membrane receptor aggregation and signaling (57). It has been shown that DHA/EPA-enriched membranes can disrupt the lipid raft structure in cancer cell membranes, leading to the depolymerization of the epidermal growth factor receptor (EGFR) from the lipid rafts and impairing the activity of its downstream signaling pathways (58). Through this action, omega-3 indirectly inhibits multiple pro-cancer signaling pathways, including the EGFR-mediated RAS/MAPK cascade and the PI3K/Akt survival pathway (59). Indeed, in models such as breast cancer, EPA/DHA treatment reduces the phosphorylation levels of kinases such as Akt and ERK, and inhibits the PI3K/Akt signaling pathway, which reduces pro-survival signaling and promotes apoptosis (50, 60). At the same time, DHA also upregulates the activity of the stress kinase p38 MAPK and increases the level of ROS in tumor cells, triggering the apoptotic program of these cells (61). In summary, omega-3 fatty acids interfere with the normal operation of multiple signaling pathways, including EGFR and PI3K/Akt, by remodeling the lipid composition and microstructure of cell membranes, inhibiting proliferation and survival signals, and enhancing apoptotic signals in tumor cells. This dual effect on membrane structure and signaling is believed to be one of the important mechanisms of omega3's anticancer effects.

Omega-3 fatty acids target inflammation and cell survival pathways to exert anticancer effects. EPA and DHA can significantly downregulate the NF-κB pathway, thereby lowering the expression of COX-2, TNF-α, and other pro-inflammatory genes in tumors. This anti-inflammatory action creates a less favorable environment for tumor progression. Additionally, ω-3 PUFAs alter membrane lipid rafts and receptor signaling: DHA/EPA enrichment in cancer cell membranes disrupts EGFR localization, which in turn impairs downstream PI3K/Akt signaling. In breast cancer cells, such membrane remodeling by ω-3 has been shown to reduce Akt and ERK phosphorylation, diminishing pro-survival signals and promoting apoptosis. Beyond apoptosis, omega-3s may induce other forms of cell death; for example, DHA was reported to trigger pyroptosis in triple-negative breast cancer cells by activating caspase-1 and gasdermin D pores (62). Collectively, these findings confirm that ω-3 fatty acids can inhibit proliferative signaling and activate cell death programs while also mitigating cancer-related inflammation.

DHA and EPA demonstrate sophisticated miRNA-mediated mechanisms involving exosomal miRNA transfer between cancer and stromal cells. DHA treatment significantly reduces miR-21 expression in MCF-7 breast cancer cells while enhancing exosomal packaging of miR-23b, miR-27b, miR-320b, and let-7a (63). These exosomal miRNAs target PLAU, AMOTL1, NRP1, and ETS2 in endothelial cells, disrupting angiogenic signaling. Animal studies show that EPA/DHA combinations achieve a 60-70% reduction in tumor size compared to ALA alone, with eight-fold greater efficacy in HER2+ mouse models. The mechanism involves time-dependent miR-21 reduction at 1, 3, and 24 h post-treatment, though PTEN protein expression remains unchanged despite miR-21 suppression, suggesting complex regulatory networks (64). Clinical trials demonstrate safety and efficacy with EPA (1.6 g) + DHA (0.8 g) daily for 12 weeks in lung cancer patients, showing improved nutritional status and suppressed inflammatory markers (CRP, TNF-α, IL-6) (63). The preclinical evidence reveals that DHA suppresses non-small-cell lung cancer via the RvD1/miR-138-5p/FOXC1 pathway, providing mechanistic support for clinical applications (Figure 4).

Cancer cachexia is a syndrome characterized by weight loss, skeletal muscle loss, and metabolic disturbances, commonly seen in patients with advanced tumors. Omega-3 fatty acids have been recognized as one of the potential nutritional interventions for cachexia due to their anti-inflammatory and metabolic modulating effects (65). First, omega-3 reduces cachexia-related muscle wasting by inhibiting inflammation. Patients with cachexia often have high levels of inflammatory factors that activate protein degradation pathways and promote muscle breakdown (66, 67). Omega3's inhibition of inflammatory signals such as NF-κB reduces the activity of the ubiquitin–proteasome pathway in muscle—for example, by downregulating the expression of the muscle-specific ubiquitin ligase MuRF-1—thereby reducing skeletal muscle protein breakdown. At the same time, the reduction of inflammation also alleviates metabolic stress on the body, resulting in a decrease in the rate of muscle catabolism (68). Second, omega-3 helps improve the nutritional metabolic status of cancer patients. Studies have shown that omega-3 can activate muscle synthesis pathways, enhance amino acid uptake by myocytes, and increase the efficiency of muscle protein synthesis (69, 70). In addition, omega-3 improves mitochondrial function and reduces inflammation-induced oxidative stress, which overall contributes to the maintenance of lean body tissue (71, 72).

Clinical trials and meta-analyses provide support for the effect of omega-3 in alleviating cachexia. A study of patients with pancreatic cancer and gastrointestinal tumors reported that during omega-3 supplementation prior to chemotherapy, patients gained an average of approximately 2.5 kilograms of body weight, which was maintained after chemotherapy was initiated (73). Another randomized controlled trial of patients undergoing surgery for esophageal cancer showed that EPA-enriched enteral nutrition, given preoperatively and postoperatively, significantly protected against lean body mass (with significantly less postoperative lean body mass loss in the EPA group), resulting in an overall weight loss of only about 1.2 kilograms (compared to 1.9 kilograms in the control group) (74). Inflammatory mediators such as TNF-alpha and IL-8 levels were also significantly reduced in these patients receiving omega-3 nutritional support, suggesting a reduction in the systemic inflammatory response. Recent systematic evaluations and dose–response meta-analyses have further demonstrated that omega-3 supplementation has a small but beneficial effect on cancer cachexia; in particular, in elderly patients with cancer cachexia, omega-3 contributes to an increase in body weight (by about 1 kg) (75). It is important to note that the effect of omega-3 on cachexia varies among studies and may depend on dosage, stage of disease, and other factors (76). There is evidence that combining omega-3s with anti-inflammatory drugs or exercise may have more significant effects. A multimodal intervention study combining omega-3 supplementation (~2 grams per day) with moderate exercise in patients with malignant lung and pancreatic cancers resulted in an average weight gain of 4.5% and an improvement in muscle mass after 6 weeks, compared with continued weight loss in the control group (77). Overall, omega-3 fatty acids, due to their anti-inflammatory, anti-catabolic properties and improved nutritional status, show potential to alleviate cancer cachexia and may help reduce muscle wasting, stabilize body weight, and improve patients' quality of life. Further large-scale clinical studies will clarify the optimal strategy for using omega-3 in the comprehensive treatment of cancer cachexia.

Phytosterols such as β-sitosterol are structurally similar to cholesterol and competitively interfere with cholesterol utilization by tumor cells (78). β-sitosterol inhibits cholesterol synthesis and uptake while promoting cholesterol efflux, thereby significantly reducing cholesterol levels in cancer cell membranes (79). The addition of β-sitosterol to colon cancer cells has been reported to reduce cell membrane cholesterol levels by about 26% (80). Depletion of cholesterol in cell membranes disrupts microdomain structures such as membrane lipid rafts, impairs the function of many raft-dependent receptors and signaling pathways, and inhibits tumor cell growth and survival (81). In addition, some alkaloids can affect cholesterol and lipid metabolism in tumor cells. Berberine has been shown to inhibit cancer cell proliferation by upregulating LDL receptors and inhibiting lipid synthesis pathways, such as fatty acid synthase, through activation of the AMPK pathway, which reduces cholesterol and lipid accumulation in tumor cells (82).

Both β-sitosterol and berberine inhibit cancer cell proliferation by inducing apoptosis through the mitochondria-mediated intrinsic pathway and blocking cell cycle progression (83). In apoptosis, β-sitosterol upregulates pro-apoptotic factors such as p53 and Bax, while downregulating anti-apoptotic proteins such as Bcl-2, leading to an increase in mitochondrial outer membrane permeability and the activation of key apoptotic enzyme cascades such as caspase-9 and −3, which induces programmed cell death (83). Furthermore, β-sitosterol increases the expression of death receptors and blocks the inhibitory effect of IAP proteins on caspases, making cancer cells more sensitive to exogenous death signals (84). Berberine also induces apoptosis via the mitochondrial pathway, promoting the release of cytochrome c from mitochondria, activating caspase-8, −9, and subsequent caspase-3 cascades, and triggering apoptosis by inhibiting the expression of Bcl-2 while increasing pro-apoptotic proteins (85). Regarding cell proliferation, these natural compounds can interfere with the activity of cell cycle regulatory proteins and induce cell cycle arrest. β-Sitosterol has been reported to inhibit a variety of cyclin-CDK complexes, upregulate the cell cycle inhibitor p27, and cause cells to arrest in the G1 phase, among others (86, 87). Berberine, on the other hand, triggers cell cycle arrest in the G0/G1 or G2/M phases by downregulating proteins such as Cyclin D1 and Cyclin E and upregulating p21, preventing cancer cells from entering the proliferation and division phases (88). By inducing apoptosis and halting the cell cycle, these two classes of compounds effectively inhibit the proliferation and growth of tumor cells.

β-Sitosterol and berberine may also exert anticancer effects by modulating inflammatory mediators and immune responses in the tumor microenvironment (89–91). Chronic inflammation contributes to tumorigenesis and development, and these natural products inhibit pro-inflammatory signals, thereby weakening the pro-inflammatory microenvironment of tumors. β-Sitosterol selectively inhibits the activity of the pro-inflammatory mediator COX-2 and reduces the levels of the oncogenic PGE₂ in tumor tissues, blocking the promotion of tumor cell proliferation by the COX-2/PGE₂ inflammatory axis (92). Meanwhile, β-sitosterol enhances the antitumor immune response. Animal experiments showed that in a melanoma mouse model, tumors tend to limit the proliferation of the host's T lymphocytes, decrease their killing function, and inhibit the activity of macrophages. However, β-sitosterol administration significantly restored T-cell and macrophage function, increased NK cell activity, enhanced the body's immune surveillance of tumors, and significantly reduced the number of lung metastases (93). Berberine also has anti-inflammatory immunomodulatory effects: studies have shown that berberine antagonizes pro-inflammatory signaling pathways and inhibits immune cells from overproducing cytokines such as TNF-α, IL-6, and IL-1β (94). Furthermore, berberine blocks IFN-γ-induced IDO1 expression by inhibiting STAT1 phosphorylation (95). Inhibiting IDO1, one of the key enzymes involved in tumor immune escape, reduces the functional suppression of T cells by tumors and improves the effector function of immune cells in the tumor microenvironment. Moreover, berberine also reduces the expression of PD-L1 on the surface of tumor cells, interfering with the mechanism by which tumor cells use the PD-1/PD-L1 pathway to evade the immune system. By downregulating PD-L1, berberine enhances the recognition and killing of cancer cells by NK cells and T lymphocytes (96). In conclusion, phytosterols and alkaloids can disrupt cancer-associated inflammatory and immune escape mechanisms by inhibiting tumor pro-inflammatory responses and enhancing antitumor immune effects, demonstrating potential clinical applications in improving the tumor microenvironment.

Phytosterols like β-sitosterol primarily act by interfering with cholesterol-dependent cell functions and oncogenic signaling. The structural mimicry of cholesterol by β-sitosterol allows it to reduce membrane cholesterol, disrupting lipid raft-associated pathways. Mechanistically, β-sitosterol can induce cancer cell apoptosis by modulating key regulators: it elevates the Bax/Bcl-2 ratio and activates caspases via the intrinsic mitochondrial pathway. Recent studies also show that β-sitosterol suppresses pro-survival signaling cascades—for instance, an oxidized β-sitosterol derivative significantly downregulated phosphorylated ERK1/2 and NF-κB p65 levels, leading to increased ceramide accumulation and apoptosis in breast and liver cancer cells (97). Furthermore, β-sitosterol attenuates IκB degradation, thereby blocking NF-κB nuclear translocation and reducing the expression of inflammation-linked growth genes (80). On the other hand, alkaloids from plants often target cell division and transcriptional machinery. A classic example is paclitaxel, which binds to β-tubulin to stabilize microtubules—this causes G2/M cell cycle arrest and triggers apoptosis (98). Paclitaxel-induced mitotic stress leads to cleavage of procaspases and activation of the caspase cascade, effectively executing programmed cell death (99). Another potent plant alkaloid, triptolide, exerts its anticancer activity by downregulating oncogenic transcription pathways. Triptolide and its analogs have been shown to inhibit NF-κB signaling, which in pancreatic cancer cells results in elevated oxidative stress, reduced Bcl-2 expression, and activation of mitochondrial apoptosis pathways (100). In essence, phytosterols and alkaloids can interfere with tumor cell survival on multiple fronts—from membrane signaling and cell cycle regulation to intrinsic apoptosis—often targeting master regulators like NF-κB, Akt/mTOR, or microtubules.

Berberine targets multiple oncogenic miRNAs, including miR-21 (50–70% reduction in HCT116 cells), miR-23a (2.5-fold increase in hepatoma cells), and suppression of the miR-17–92 cluster in multiple myeloma. The compound regulates miRNA expression through AMPK signaling pathway activation and chromatin remodeling, with PDCD4 protein levels increasing by 60% following miR-21 inhibition (101). Capsaicin demonstrates TRPV1-mediated miRNA modulation, with miR-449a significantly upregulated (3–4-fold) in prostate cancer cells, promoting androgen receptor degradation (40–50% reduction) (102). The compound enhances miR-34a expression two-fold in non-small-cell lung cancer, promoting Bax-dependent apoptosis through calcium influx and ROS generation (103). Caffeine affects colon carcinogenesis through miR-21a-5p suppression (fold change >2) and activates miR-30c/miR-96, targeting KRAS expression (30–40% reduction) (104). Combination treatments with chlorogenic acid show synergistic miRNA modulation affecting miR-144-3p (2.2-fold upregulation) in hepatocarcinogenesis prevention studies (105).

Isothiocyanates (ITCs) are bioactive compounds derived from glucosinolate precursors abundant in cruciferous vegetables (e.g., broccoli and watercress) (106). Notable examples include sulforaphane (SFN) from broccoli and phenethyl isothiocyanate (PEITC) from watercress (107). These phytochemicals have been widely linked to cancer prevention and therapy due to their broad spectrum of anticancer mechanisms. ITCs can trigger programmed cell death in cancer cells and halt their proliferation. Numerous in vitro studies show that ITCs induce apoptosis via both intrinsic and extrinsic pathways (108)—for instance, through caspase activation (109), mitochondrial dysfunction (110), and oxidative stress generation (111). A recent chemical proteomics study identified the pro-apoptotic Bcl-2 family protein BID as a direct covalent target of PEITC; its activation leads to mitochondrial outer membrane permeabilization and robust apoptosis in tumor cells (112). Consistently, compounds like SFN are known to cause G2/M cell cycle arrest in various cancer cell lines, thereby suppressing tumor growth (113). The promotion of apoptotic cell death and cell cycle inhibition is a central antitumor mechanism of ITCs in many cancer types (114).

ITCs are potent activators of the Keap1–Nrf2 signaling pathway, which upregulates cytoprotective genes. By modifying Keap1 cysteine residues, ITCs stabilize Nrf2, leading to enhanced transcription of antioxidant response elements and phase II detoxification enzymes (113). Through this mechanism, ITCs bolster cellular defenses against oxidative damage and help eliminate carcinogens. For example, SFN is one of the most potent naturally occurring inducers of phase II enzymes, contributing to chemoprevention (115). This antioxidative detoxification mechanism protects normal cells from genotoxic stress; however, it can also create a reductive microenvironment that paradoxically may aid advanced tumors, reflecting the complex dual role of Nrf2 in cancer. Overall, the Nrf2-mediated induction of protective enzymes is a major pathway through which ITCs exert cancer-preventive effects (116).

A distinctive molecular action of ITCs, especially SFN, is the inhibition of histone deacetylases (HDACs). SFN functions as an HDAC inhibitor in mammalian cells, leading to increased histone acetylation and re-expression of epigenetically silenced tumor suppressor genes (117). This epigenetic reprogramming is partly linked with other ITC effects: HDAC inhibition by SFN has been associated with the suppression of phase I carcinogen-activating enzymes and the concurrent induction of phase II detoxifiers (118). In cancer models, SFN's HDAC-inhibitory activity has been shown to reactivate pathways that induce cell cycle arrest and apoptosis (119). Likewise, PEITC and other ITCs can influence DNA methylation and non-coding RNA expression, further contributing to the epigenetic regulation of cancer cell fate (120). The ability to remodel the epigenetic landscape underscores the multitargeted anticancer potential of ITCs.

ITCs also exert anticancer effects by altering the tumor microenvironment. They have demonstrated anti-inflammatory activity; notably, SFN suppresses the NF-κB pathway, reducing pro-inflammatory cytokine production that otherwise supports tumor growth and immune evasion (121). ITCs can inhibit angiogenesis and metastasis; early studies showed that ITCs block new blood vessel formation and epithelial–mesenchymal transition (EMT) in tumors (122). For example, SFN and PEITC have been reported to downregulate matrix metalloproteinases and other mediators of invasion, thereby impairing cancer cell migration and metastatic spread (123). Additionally, ITCs may enhance antitumor immunity: in experimental models, they promote the activity and proliferation of immune effector cells such as natural killer and T cells, contributing to immunosurveillance against tumors (113). By modulating inflammatory pathways, blood supply, and immune cell responses in the tumor microenvironment, ITCs create conditions that are less favorable for cancer progression.

Sulforaphane demonstrates extensive miRNA effects with well-characterized targets across multiple cancer types. Zhang et al. (124) identified the upregulation of miR-3919 in prostate cancer cells (PC-3, DU145), where the miR-3919/DJ-1 axis mediates antitumor effects. In nasopharyngeal cancer, sulforaphane upregulates miR-124-3p, which directly targets STAT3 signaling and reduces cancer stem cell markers, including β-catenin, Nanog, and Oct3/4 in HONE1, SUN1, CNE1, and CNE2 cell lines (125). Phenethyl isothiocyanate (PEITC) specifically targets the miR-194/BMP1 axis in prostate cancer. Oligonucleotide microarray analysis followed by qPCR validation revealed the upregulation of miR-194 in LNCaP and PC3 cells, with direct targeting of bone morphogenetic protein 1 (BMP1) in the 3'-UTR region. This mechanism decreases MMP2 and MMP9 expression, effectively suppressing cell invasion through Matrigel (126). Benzyl isothiocyanate (BITC) demonstrates unique miRNA restoration in bladder cancer. Recent comprehensive studies using qPCR microarray identified 79 aberrantly expressed miRNAs, with miR-99a-5p showing dose-dependent upregulation in 5637, RT4, HT1376, HT1197, and T24 cell lines. Validation studies confirmed the direct targeting of IGF1R, FGFR3, and mTOR, with antisense miR-99a-5p sequences reversing BITC effects (127) (Figure 5).

Given their multitargeted mechanisms and low toxicity profiles, ITCs are actively explored in clinical settings as chemopreventive or adjunct therapeutic agents (128). Epidemiological data link high cruciferous vegetable intake with reduced cancer incidence in humans (113). More directly, early-phase clinical trials with purified ITCs or ITC-rich preparations have yielded encouraging results. In a recent randomized Phase II trial, a broccoli sprout-derived SFN supplement given to former smokers for 12 months significantly decreased the Ki-67 proliferative index in their bronchial epithelium compared to an increase in the placebo group. No serious adverse events were reported, underscoring the tolerability of dietary ITC. Although that trial did not reverse pre-neoplastic changes, the reduction in cell proliferation supports further investigation of SFN for lung cancer chemoprevention (129). Additionally, combination therapy studies indicate that ITCs can sensitize tumors to conventional chemotherapy and overcome drug resistance, thereby improving therapeutic outcomes when used as adjuncts (130). It is important to note that ITCs exhibit a hormetic dose-response: low dietary doses may have negligible or even protective effects on cells, whereas higher pharmacological doses are required for cytotoxic antitumor activity (113). This biphasic behavior necessitates careful optimization of dosing in any future clinical applications. Nevertheless, the consensus of recent literature is that isothiocyanates are promising cancer-fighting phytochemicals with potential roles in both cancer prevention and therapy. Their ability to target multiple pathways—from initiating apoptosis and detoxifying carcinogens to reprogramming epigenetics and the tumor microenvironment—positions ITCs as attractive candidates for integrative oncology approaches (113).

Polysaccharides are high-molecular-weight carbohydrate compounds abundant in functional foods such as mushrooms, algae, and medicinal herbs. Representative anticancer polysaccharides include β-glucans (from yeast and fungi) and fucoidan (from brown seaweed), among others. These bioactive polysaccharides exhibit multifaceted anticancer mechanisms. Induction of apoptosis is a major pathway—many polysaccharides trigger caspase-dependent programmed cell death in tumor cells (131). For example, β-glucans from fungi can activate initiator caspase-8 and effector caspase-3, leading to mitochondrial cytochrome C release and apoptosis in cancer cells (132). Polysaccharides also cause cell cycle arrest, thereby halting the proliferation of malignant cells (133). In parallel, they exert significant immunomodulatory effects: polysaccharides stimulate the immune system's antitumor response by activating macrophages, T lymphocytes, natural killer cells, and dendritic cells, and by promoting the release of cytokines such as TNF-α, IFN-γ, and IL-2 (134). This immune regulation helps the body recognize and destroy cancer cells more effectively. Indeed, enhancing host immunity is considered a primary antitumor pathway for plant polysaccharides (135).

Another important mechanism is oxidative stress regulation. Polysaccharides often possess antioxidant properties that allow them to modulate ROS levels and related signaling. By scavenging excessive ROS, polysaccharides can prevent the activation of pro-tumorigenic pathways (e.g., NF-κB and MAPK) that are driven by oxidative stress (136). Some polysaccharides can also induce mild ROS generation in cancer cells, pushing them beyond their oxidative threshold and triggering cell death, all while protecting normal cells—an effect linked to the activation of endogenous antioxidant pathways like Nrf2 (137). Furthermore, polysaccharides interfere with key signaling pathways that regulate survival, metastasis, and angiogenesis in tumors. For instance, a dandelion-derived polysaccharide was shown to inhibit the PI3K/Akt pathway, downregulating HIF-1α and VEGF expression, and thereby suppressing tumor angiogenesis (138). Many polysaccharides also inhibit NF-κB signaling, which in turn reduces pro-inflammatory mediators in the tumor microenvironment and sensitizes cancer cells to immune attack (139). In addition, the marine polysaccharide fucoidan exemplifies broad pathway modulation: it can induce cancer cell apoptosis and cell cycle arrest, block metastasis and angiogenesis, and modulate various signaling molecules involved in tumor growth (133).

Notably, emerging research indicates that polysaccharides can act as epigenetic modulators in cancer. Certain plant-derived polysaccharides (e.g., from Astragalus or Ganoderma lucidum) promote DNA demethylation of tumor suppressor genes via TET enzymes, inhibit oncogenic histone-modifying enzymes, and regulate cancer-related microRNAs (140). Through these epigenetic reprogramming actions, polysaccharides may reactivate silenced tumor suppressor pathways and impede tumor progression. This epigenetic influence adds a new dimension to their anticancer activity. Moreover, polysaccharides often work synergistically with conventional therapies. Clinically, mushroom β-glucans have been used as adjuvants to chemotherapy and radiotherapy to boost immune function; co-administration of fungal β-glucan has been reported to mitigate therapy-induced leukopenia and immune suppression, improving patient recovery (141). Polysaccharides from Angelica sinensis similarly protected hematopoietic cells from cyclophosphamide toxicity (142). Preclinical studies confirm that combining polysaccharides with chemotherapeutics can enhance tumor killing while reducing side effects through immune modulation and tissue protection (140). For example, Astragalus polysaccharide (APS) was shown to inhibit the formation of the pre-metastatic niche in lung cancer by blocking the S1PR1/STAT3 signaling pathway, thereby preventing metastasis when used alongside standard treatment (143). In addition, polysaccharides hold promise as drug delivery vehicles in cancer therapy due to their biocompatibility and tunable structure. Natural polymers like chitosan, pectin, and alginate are being developed as carriers in nanoparticle and hydrogel systems to deliver anticancer drugs more specifically to tumors. Such polysaccharide-based delivery systems can improve drug stability and targeting, enhancing therapeutic efficacy. Overall, polysaccharides from functional foods exert anticancer effects through a combination of apoptotic induction, immune activation, oxidative stress attenuation, and pathway interference, with additional roles in epigenetic regulation and supportive therapy. These diverse mechanisms underscore their potential as nontoxic adjuvants and therapeutic agents in future cancer treatment strategies (140).

Fucoidan exhibits dual miRNA regulation affecting both tumor-suppressive and oncogenic pathways. Wu et al. and Yan et al. demonstrated the upregulation of miR-29c and the downregulation of miR-17-5p in breast cancer (MCF-7, MDA-MB-231) and hepatocellular carcinoma (SMMC-7721) cells. The upregulation of miR-29c targets ADAM12 and inhibits EMT, while the downregulation of miR-17-5p restores PTEN pathway function (144). Astragalus polysaccharides (APS) show cancer-specific miRNA targeting. Tao et al. identified the upregulation of miR-195-5p in non-small-cell lung cancer, which leads to suppressed proliferation and invasion (145). In prostate cancer, a study demonstrated that APS-mediated upregulation of miR-133a in DU145 cells effectively inhibited proliferation, invasion, and migration by targeting oncogenic pathways (146). Chitosan-based delivery systems enable precise miRNA modulation. Chitosan nanoplexes have been developed for the targeted delivery of miR-200c and miR-141 to breast cancer cells (MCF-7, MDA-MB-231, MDA-MB-435), successfully restoring miRNA expression levels to those observed in non-cancerous cells. Advanced formulations utilizing GE11 peptide-conjugated chitosan nanoparticles can specifically target EGFR-overexpressing triple-negative breast cancer cells, leading to the downregulation of miR-21 and inhibition of the AKT/ERK signaling axis (147).

Phenolic acids are a major class of plant-derived polyphenols (non-flavonoid type) widely present in fruits, vegetables, teas, coffee, and other foods. Key representatives include gallic acid (GA) (a hydroxybenzoic acid found in berries, tea, and other sources) and caffeic acid (a hydroxycinnamic acid abundant in coffee, apples, and herbs), along with others like ferulic and p-coumaric acids (148). These compounds are well known for their potent antioxidant properties and have demonstrated broad-spectrum anticancer activities. Phenolic acids combat cancer through multiple molecular mechanisms. They induce apoptosis in tumor cells via both intrinsic and extrinsic pathways, often associated with the activation of pro-apoptotic proteins and caspase cascades. For example, GA can trigger mitochondrial apoptotic signals: it upregulates Bax, downregulates Bcl-2, and activates caspase-9 and −3, leading to programmed cell death in various carcinoma cells (148). They also cause cell cycle arrest; GA has been shown to halt cancer cell cycles at the S or G2/M phase, thereby suppressing proliferation (149). In addition, phenolic acids exhibit anti-angiogenic and anti-metastatic effects. In vivo studies indicate these compounds can inhibit tumor neovascularization and invasion; for instance, phenolics were observed to reduce VEGF levels and MMP activity, thereby impairing angiogenesis and metastatic spread. Caffeic acid and its derivatives can block pro-angiogenic signaling: caffeic acid phenethyl ester (CAPE) has been reported to suppress STAT3-mediated VEGF expression, inhibiting tumor angiogenesis in renal carcinoma models. Likewise, caffeic acid itself directly inhibited ERK1/2 (MAPK) activity in melanoma and epidermoid carcinoma cells, disrupting a key pathway that promotes tumor growth and migration (150).

Phenolic acids strongly modulate cellular signaling pathways that govern survival and inflammation in cancer. A prominent example is their inhibition of the PI3K/Akt pathway—GA treatment in lung cancer cells led to downregulation of PI3K/Akt alongside increased p53 levels, which in turn activated downstream executioner caspases and cell cycle inhibitors (p21Cip1/p27Kip1), culminating in apoptosis and growth arrest (151). Many phenolic acids are also known to suppress the NF-κB pathway, thereby reducing pro-inflammatory cytokines in the tumor microenvironment and sensitizing cancer cells to immune attack (150). CAPE, for instance, is a well-documented NF-κB inhibitor and has demonstrated antitumor efficacy by blocking NF-κB–driven survival signals in prostate and ovarian cancer cells (152). In addition to inhibiting oncogenic signals, these compounds often activate stress–response pathways in cells. As antioxidants, phenolic acids typically activate the Nrf2 pathway in normal cells, enhancing cytoprotective antioxidant enzymes. This effect can protect healthy tissues from oxidative damage and contributes to chemoprevention (153). Interestingly, recent research has highlighted a dual role for Nrf2 in cancer: while basal Nrf2 activity aids normal cell defense, cancer cells can exploit Nrf2 for chemoresistance. Certain phenolic compounds can inhibit Nrf2 in tumor cells, stripping them of antioxidant defenses (154). This targeted Nrf2 inhibition drives cancer cells into lethal oxidative stress and can improve the efficacy of chemo-radiotherapy. Thus, phenolic acids can both quench excess radicals to prevent cancer initiation and, in established tumors, undermine the antioxidant shield of cancer cells.

Phenolic acids also exert epigenetic effects that restore normal regulatory controls in cancer cells. They can influence DNA methylation and histone modifications that are dysregulated in tumors. For example, GA has been shown to bind and stabilize G-quadruplex DNA structures in oncogene promoters (such as c-Myc), leading to transcriptional downregulation of those genes (155). Such an interaction essentially mimics telomerase/telomere inhibition and triggers nucleolar stress, contributing to tumor growth suppression. Indeed, GA was found to selectively kill colorectal cancer cells in part by inducing G-quadruplex-mediated telomeric dysfunction (156). More broadly, dietary polyphenols like gallic and ferulic acid are recognized for reversing aberrant epigenetic marks—they can inhibit DNA methyltransferases or HDACs, reactivating silenced tumor suppressor genes (153). Through these mechanisms, phenolic acids help reprogram cancer cells to a less aggressive state.

Ferulic acid specifically targets the miR-221/TP53INP1 autophagy axis. Sweed et al. demonstrated significant downregulation of miR-221 in colorectal cancer (Caco-2 cells), leading to upregulation of TP53INP1 (p < 0.0001) and enhanced autophagy-mediated cell death with S-phase cell cycle arrest (157). Gallic acid affects complex miRNA regulatory networks. Recent RNA-sequencing analysis revealed 13 upstream miRNAs in gallic acid's therapeutic network in cervical cancer, with regulatory networks involving lncRNA/circRNA–miRNA–mRNA pathways targeting genes such as CDC20, DLGAP5, and KIF20A (158). In colorectal cancer, low-dose gallic acid ( ≤ 100 μM) reduces invasiveness through specific miRNA regulation without inducing cell death (159). Chlorogenic acid induces cancer differentiation through coordinated miRNA regulation. Key miRNAs include miR-20a, miR-93, and miR-106b, which regulate p21 targeting through the seed sequence AAGUGC. Dual luciferase reporter assays confirmed miRNA-p21 interactions, with upregulation of the NFATC2 and NFATC3 genes in immune pathways (160).

Notably, phenolic acids can enhance conventional cancer therapies and have shown synergistic effects with chemo-radiotherapy. GA, for instance, significantly boosted the efficacy of standard chemotherapeutics (e.g., cisplatin, doxorubicin, and 5-FU) when combined with gamma irradiation in oral cancer cells, by promoting superoxide-dependent apoptosis and blocking protective autophagy in an Nrf2-dependent manner (161). This combination led to increased cancer cell kill rates, illustrating GA's potential as a radiosensitizer. Similarly, caffeic acid has been reported to synergize with paclitaxel: co-treatment of caffeic acid with low-dose paclitaxel inhibited non-small-cell lung cancer growth more effectively than paclitaxel alone, with a marked increase in apoptosis and suppression of proliferative signals in tumor cells (162). Phenolic acids may also mitigate chemotherapy side effects through their antioxidant and anti-inflammatory properties, thereby improving therapeutic indices. In terms of drug delivery, these small-molecule phytochemicals can be chemically modified or encapsulated to enhance their bioavailability. For example, caffeic acid's derivative CAPE has been formulated in nanocarriers (such as γ-cyclodextrin inclusion complexes) to improve its stability and anticancer potency (148). Such strategies aim to harness phenolic acids in more effective forms for clinical use.

Flavonols are a prominent subclass of dietary flavonoids found abundantly in fruits, vegetables, tea, and wine. Representative flavonols include quercetin, kaempferol, myricetin, fisetin, isorhamnetin, and morin, which are present in foods such as onions, berries, apples, brassica vegetables, and capers (163). These compounds exhibit broad-spectrum anticancer activities through multiple mechanisms. Antioxidant and free radical scavenging are key properties—flavonols directly neutralize ROS and upregulate cellular antioxidant defenses, protecting DNA from oxidative damage and mutagenesis (163). Paradoxically, in the context of tumors, flavonols can exert pro-oxidant effects at higher concentrations, elevating ROS within cancer cells to trigger oxidative stress-induced apoptosis. Flavonols also potently induce apoptosis in cancer cells via the intrinsic (mitochondrial) pathway. Quercetin and related flavonols modulate Bcl-2 family proteins, increasing pro-apoptotic Bax and reducing anti-apoptotic Bcl-2, which promotes cytochrome c release and caspase-3/9 activation (164). They can also activate extrinsic apoptosis by upregulating death receptors or downstream effectors. In parallel, flavonols cause cell cycle arrest in various phases to halt cancer cell proliferation. For example, quercetin and fisetin have been shown to induce G0/G1 or G2/M phase arrest by downregulating cyclins (Cyclin B, D, E) and cyclin-dependent kinases (CDK1, CDK2, CDK4/6) while upregulating CDK inhibitors like p21Cip1 and p27Kip1 (165). This disruption of cell cycle progression limits the unchecked growth of cancer cells.

Molecular signaling pathways central to cancer cell survival are major targets of flavonols. Quercetin is exemplary in interfering with pro-oncogenic signaling: it inhibits the PI3K/Akt/mTOR and MAPK/ERK pathways, thereby suppressing downstream survival signals and proliferative drivers. By inhibiting Akt and ERK phosphorylation, quercetin triggers apoptosis and growth arrest selectively in tumor cells. Flavonols also block the continuous activation of transcription factors like NF-κB and STAT3 that promote tumor progression. Quercetin has been shown to downregulate NF-κB activity, leading to reduced expression of inflammatory cytokines and survival genes, and to modulate JAK/STAT signaling—enhancing immune recognition of cancer cells while diminishing immunosuppressive signals (164). Notably, a recent study in hepatocellular carcinoma cells found that quercetin induced robust apoptosis by inhibiting the PI3K/Akt/mTOR axis (via downregulation of P4HA2, a proline hydroxylase) and activating p53-dependent death pathways. Many flavonols (e.g., kaempferol and isorhamnetin) similarly target multiple nodes in signaling networks to shift the balance toward cancer cell death and away from survival (163). In addition, flavonols can inhibit tumor angiogenesis by downregulating VEGF, HIF-1α, and other angiogenic factors, starving tumors of blood supply. Quercetin and kaempferol have each been reported to reduce VEGF secretion and disrupt new blood vessel formation in tumor models (166). They also suppress metastasis through anti-invasive and anti-migratory effects—for instance, by inhibiting matrix metalloproteinases (MMP-2, MMP-9) and reversing EMT. Through attenuation of NF-κB and AP-1 signaling, flavonols reduce MMP production, thereby impeding the degradation of the extracellular matrix required for metastasis (167).

Some flavonols (e.g., fisetin) are reported to upregulate E-cadherin and tight junction proteins, counteracting EMT and metastatic spread. Moreover, flavonols exert immunomodulatory effects that enhance antitumor immunity. By curbing chronic inflammation (via NF-κB inhibition) and modulating the tumor microenvironment, they create conditions more favorable for immune cell attack (164). Quercetin's suppression of STAT3, for example, can boost cytotoxic T-cell activity and reduce immune evasion, since STAT3 in tumors often drives the production of immunosuppressive factors. Flavonols have also been noted to influence macrophage polarization and enhance the efficacy of immune checkpoint therapies in preclinical studies (163). Finally, flavonols may induce epigenetic modifications in cancer cells. Some act as epigenetic modulators by inhibiting HDACs or DNA methyltransferases or by altering microRNA expression, thereby reactivating silenced tumor suppressor genes. For instance, quercetin has been identified as a cancer epigenetic regulator that can restore p53 activity by disrupting oncogenic protein interactions (e.g., blocking the YY1–p53 complex) and increasing pro-apoptotic gene expression (168). Through this multifaceted array of actions—antioxidant, pro-apoptotic, anti-proliferative, anti-angiogenic, anti-metastatic, immunomodulatory, and epigenetic—flavonols demonstrate significant potential in cancer prevention and therapy. Notably, their relatively low toxicity and presence in everyday foods make them attractive as chemopreventive agents. Ongoing research, including nanocarrier-based delivery of quercetin, aims to overcome bioavailability issues and translate flavonols into effective adjuvant cancer treatments. The accumulating evidence supports flavonols as key functional food ingredients that can target multiple hallmarks of cancer simultaneously, contributing to reduced tumor growth and enhanced responses to conventional therapies (163).

Quercetin demonstrates broad-spectrum miRNA effects across multiple cancer types. In cervical cancer (HeLa cells), quercetin upregulates tumor suppressor miRNAs miR-26b, miR-126, and miR-320a, with miR-320a directly targeting β-catenin (CTNNB1) to inhibit the Wnt pathway. Clinical validation studies in 264 lung cancer patients showed a correlation between dietary quercetin and higher expression of the let-7 family and miR-146a (169). Kaempferol and fisetin exhibit synergistic miRNA modulation. Kubina et al. identified IC50 values of 38.85 μM (SCC-9) and 62.34 μM (SCC-25) in head and neck cancer cells, demonstrating dose-dependent apoptosis induction and G1 phase cell cycle arrest (170). The mechanism involves modulation of the ERK signaling pathway and inhibition of the NF-κB pathway. Myricetin shows consistent anti-neoplastic activity with 9.62-9.74% absolute bioavailability, demonstrating colorectal cancer prevention through the inhibition of tumorigenesis and reduction of polyp size. The mechanism involves activation of the apoptosis pathway, anti-angiogenic effects, and inhibition of matrix metalloproteinases (171).

Amide-bearing compounds from edible plants—particularly capsaicinoids and related alkylamides—have emerged as potent anticancer agents. The most prominent example is capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the spicy component of chili peppers (Capsicum species). Another is piperine, the pungent alkaloid in black pepper (Piper nigrum), along with analogs like piperlongumine from long pepper. These dietary amides exhibit multifaceted antitumor activities. Capsaicin, in particular, has been widely studied and influences numerous cancer hallmarks. One major mechanism is the induction of apoptosis. Capsaicin can trigger programmed cell death via both extrinsic and intrinsic pathways. It binds to and activates the TRPV1 vanilloid receptor—a calcium-permeable ion channel—on cancer cells, leading to a surge in intracellular Ca²⁺. This Ca²⁺ overload precipitates mitochondrial dysfunction: capsaicin causes a loss of mitochondrial membrane potential, opening of the permeability transition pore, and release of cytochrome c, thereby activating the caspase cascade and resulting in apoptotic cell death (172).

In human anaplastic thyroid carcinoma and glioma cells, capsaicin-induced Ca2+ influx through TRPV1 has been shown to initiate p38 MAPK signaling and mitochondrial apoptosis, effects abrogated by TRPV1 antagonists (173). Capsaicin can also induce apoptosis independently of TRPV1 through direct modulation of stress and survival kinases. It has been found to activate the pro-apoptotic kinase AMPK and the tumor suppressor p53, as well as c-Jun N-terminal kinase (JNK), leading to apoptosis even when TRPV1 is blocked (174). Additionally, capsaicin directly interacts with the electron transport chain in mitochondria, enhancing ROS generation and promoting a change in the Bax/Bcl-2 ratio in favor of apoptosis (175). For example, in pancreatic cancer models, capsaicin raised intracellular ROS and upregulated Bax while downregulating Bcl-2, culminating in caspase-dependent apoptosis in vitro and in vivo (172). Piperine and related pepper alkaloids likewise induce apoptosis by increasing mitochondrial oxidative stress and activating executioner caspases (103). These amides often cause cancer cells to undergo morphological apoptosis (cell shrinkage, chromatin condensation) without harming normal cells at equivalent doses (176).

Cell cycle arrest is another anticancer mechanism of amide compounds. Capsaicin has demonstrated the ability to halt cell cycle progression in multiple cancer types, preventing proliferation. In breast and oral carcinoma cells, capsaicin treatment has been shown to cause a G1-phase arrest by downregulating cyclin D/CDK4/6 and upregulating the CDK inhibitor p21, whereas in other models (e.g., KB nasopharyngeal carcinoma, MCF-7 breast cancer), it induced a G2/M arrest associated with reduced Cyclin B and CDK1 levels (172). The molecular targets underlying capsaicin's cell cycle effects include the E2F–cyclin pathway and sirtuin signaling. Capsaicin has been reported to inhibit oncogenic tNOX (ENOX2), leading to decreased NAD+ and SIRT1 activity, which in turn stabilized p53 and c-Myc—enforcing the G1/S checkpoint and blocking cell cycle progression (165). In bladder cancer cells, capsaicin similarly downregulated SIRT1 and upregulated p53, contributing to a sustained arrest and subsequent apoptosis (177). Through such modulation of cell cycle regulators and checkpoint control, capsaicin and piperine limit the proliferative capacity of cancer cells.

Dietary amides also exhibit significant antioxidant and anti-inflammatory actions that contribute to cancer prevention. At lower doses, capsaicin functions as an antioxidant in normal tissues; it can directly neutralize free radicals (e.g., ABTS and DPPH radicals in chemical assays) and elevate cellular antioxidant enzymes. Capsaicin has been shown to induce the Nrf2/ARE pathway, leading to increased expression of heme oxygenase-1, glutathione-S-transferase, superoxide dismutase, and catalase (178, 179). This Nrf2-mediated antioxidant response helps protect cells from DNA damage caused by carcinogens and ROS. In fact, capsaicin's chemopreventive effects invivo have been linked to its ability to inhibit carcinogen activation (e.g., by suppressing CYP450 enzymes that produce reactive metabolites) and to mitigate oxidative stress and inflammation in tissues (180). On the other hand, within established tumors, capsaicin often acts as a pro-oxidant and anti-inflammatory agent to damage cancer cells and their microenvironment. It inhibits chronic inflammatory signaling by targeting NF-κB, a master regulator of inflammation and cell survival.

Capsaicin can block the nuclear translocation of NF-κB and downregulate NF-κB–controlled genes (COX-2, TNF-α, IL-6), thereby reducing the pro-inflammatory environment that fosters tumor growth (167). For example, in H. pylori-associated gastric tumorigenesis, capsaicin's known inhibition of NF-κB led to lower iNOS and cytokine levels, alleviating inflammation and mucosal damage (181). By quelling inflammation, capsaicin not only directly impairs tumor cell proliferation but also may restore immune surveillance. Notably, capsaicin has been identified as a selective inhibitor of STAT3 signaling in tumors (182). It promotes the lysosomal degradation of STAT3 protein, as recently demonstrated in vitro, thereby shutting off a pathway that tumors use for immune evasion and survival (183). Through STAT3 inhibition, capsaicin can reduce the expression of immunosuppressive factors and increase cancer cell visibility to the immune system. This aligns with reports that capsaicin's antitumor efficacy involves enhancing cytotoxic T lymphocyte activity and promoting an immunogenic tumor microenvironment (184). Capsaicin and piperine may thus act as immune modulators, reducing the chronic inflammation that drives many cancers while boosting antitumor immune responses.

In addition, amide phytochemicals interfere with angiogenesis and metastasis, which are critical processes for cancer progression. Capsaicin has shown remarkable anti-angiogenic activity by inhibiting the formation of new blood vessels that supply tumors. In both cultured endothelial cells and animal tumor models, capsaicin treatment reduced VEGF production and blocked angiogenic signaling (185). One study found that capsaicin activated a p53-SMAR1 autoregulatory loop in lung cancer cells, leading to the downregulation of VEGF and subsequent impairment of angiogenesis (185). Correspondingly, capsaicin suppressed in vitro tube formation of endothelial cells and in vivo microvessel sprouting in implanted tumors (182). This results in nutrient deprivation of the tumor and inhibited growth of secondary lesions. These amides also impede metastatic spread. Capsaicin targets multiple steps of the metastatic cascade by reducing cancer cell motility, invasion, and colony formation at distant sites. Mechanistically, capsaicin downregulates MMP-9 and MMP-2, enzymes that degrade extracellular matrix barriers, by suppressing key signaling pathways such as AMPK–NF-κB, EGFR–FAK/Akt, PKC/Raf/ERK, and p38 MAPK/AP-1 (186). In melanoma and thyroid carcinoma models, capsaicin's inhibition of PI3K/Akt/Rac1 signaling was identified as a primary reason for its anti-migratory effect (187). Capsaicin also upregulates the tight junction protein claudin-3 and reverses EMT markers in aggressive esophageal cancer cells, thereby restoring epithelial characteristics and reducing invasion (166). In vivo evidence from an orthotopic prostate cancer model demonstrated that capsaicin treatment significantly reduced metastatic tumor burden, corroborating its anti-metastatic efficacy in whole organisms (166). Piperine has similarly shown anti-metastatic effects, for instance by inhibiting TGF-β-induced EMT and reducing metastatic lung nodules in breast cancer models (103).

Capsaicin demonstrates direct miRNA restoration in cancer cells. Multiple studies confirm the upregulation of miR-449a in prostate cancer cells (C4-2 and LNCaP lines), where capsaicin treatment directly increases miR-449a expression. The mechanism involves miR-449a targeting of the androgen receptor (AR)3'UTR, leading to AR degradation and enhanced sensitivity to treatment (102). Piperine exhibits potent epigenetic miRNA regulation. Recent combination studies show that piperine plus thymoquinone treatment increases miR-29c expression 53–58-fold in HepG2 and MDA-MB-231 cells, with target validation showing the downregulation of DNMT3B and HDAC3 (188). The mechanism involves the inhibition of the Wnt/β-catenin pathway and modulation of PI3K/Akt/mTOR signaling (189). Piperlongumine affects multiple miRNAs through ROS-dependent mechanisms. Key targets include the downregulation of miR-27a, miR-20a, and miR-17 through ROS-dependent cMyc repression, leading to the induction of ZBTB10 and ZBTB4 transcriptional repressors(190). In lung cancer studies, miR-34b-3p upregulation targets TGFBR1 (transforming growth factor beta type I receptor) in A549 and H1299 cell lines (191) (Table 1).

The LIBRE-1 study provides the most comprehensive evidence for genetically informed nutritional interventions, involving 366 BRCA1/2 mutation carriers in a multicenter randomized controlled trial (203). Participants following Mediterranean diet education showed significant reductions in IGF-I levels and improved adherence to protective dietary patterns, with reduced consumption of red meat and processed foods while increasing whole grains, legumes, and nuts (203). This first large-scale intervention demonstrated the clinical feasibility of genetic risk-based nutritional recommendations for cancer prevention. MTHFR gene polymorphisms have emerged as critical biomarkers for precision nutrition, with the C677T variant present in 47% of Hispanic and 36% of European populations (204). Individuals with the TT genotype require 1.5–2 times higher folate intake (600–800 μg daily) due to a 70% reduction in enzyme activity (205), as validated in the China Stroke Primary Prevention Trial involving 16,413 participants. The clinical significance extends beyond supplementation, with MTHFR expression levels correlating with immune infiltration and checkpoint blockade response across 44 cancer types (206). TP53 tumor suppressor gene interactions represent another validated target for personalized nutrition. The rs1042522 G allele is associated with a significantly increased breast cancer risk (OR = 2.98, p < 0.001), while carriers show differential responses to antioxidant supplementation (204). Ongoing clinical trials are testing selenium and vitamin E combinations specifically in TP53 variant carriers, demonstrating the movement from association studies to targeted therapeutic interventions.

The largest multicenter microbiome study in cancer involved 438 melanoma patients across the UK, Netherlands, and Spain, identifying three bacterial species consistently associated with enhanced immunotherapy response: Bifidobacterium pseudocatenulatum, Roseburia spp., and Akkermansia muciniphila (207). Survival outcomes nearly doubled between high vs. low beneficial microbe subgroups, with microbiome composition influenced by dietary fiber intake, proton pump inhibitor use, and individual constitutional factors. Strain-level microbiome analysis has proven superior to species-level profiling for clinical applications. A Phase 2 trial with 106 diverse cancer patients demonstrated that strain-resolved analysis improved machine learning predictions of immunotherapy response and 12-month progression-free survival compared to conventional taxonomic approaches (208, 209). This precision enables cancer type-agnostic but therapy-specific treatment selections based on individual microbial signatures. High-fiber dietary interventions show remarkable specificity in their microbiome effects. Studies demonstrate that a daily fiber intake of ≥20 g without commercial probiotics produces optimal immunotherapy response rates through enhanced short-chain fatty acid production (210). Fiber-derived butyrate, propionate, and acetate enhance antitumor T-cell responses through SCFA-mediated histone deacetylase inhibition, providing mechanistic validation for microbiome-guided dietary recommendations (211, 212).

Artificial intelligence applications in precision nutrition have achieved remarkable sophistication, with deep learning architectures using convolutional neural networks with up to 295 layers achieving 86% accuracy in food recognition and nutritional analysis (213, 214). The Diet Engine platform combines computer vision, natural language processing, and continuous glucose monitoring for real-time personalized dietary recommendations tailored to cancer treatment protocols. Multi-omic data integration platforms represent the cutting edge of precision nutrition technology. The MintTea platform uses canonical correlation analysis extensions to identify disease-associated modules that combine genomics, microbiome, and metabolomics data, demonstrating effectiveness in colorectal cancer studies. These platforms achieve high predictive power through significant cross-omic correlations, enabling unprecedented personalization of nutritional interventions (215). The European Union's ONCOBIOME network exemplifies international collaboration in data integration, combining gut microbiome, metabolism, and immune response data across multiple cohorts and cancer types. This infrastructure supports the development of oncomicrobiome signatures for diagnosis, prognosis, and treatment response prediction (216).

BRCA-associated nutrient interactions demonstrate clinically actionable gene–diet relationships. Moderate vitamin B12 supplementation may provide a 20–40% reduction in breast cancer risk for BRCA mutation carriers, with genetic testing guiding supplementation recommendations. Components of olive oil suppress HER2 expression through epigenetic mechanisms, particularly benefiting BRCA carriers at risk for HER2-positive breast cancer through Mediterranean diet patterns that include 3–4 tablespoons of daily extra virgin olive oil. The GECCO Consortium analysis of 9,287 colorectal cancer cases identified the rs4143094 variant near the GATA3 gene as significantly modifying processed meat cancer risk (217). This discovery enables risk stratification for dietary counseling based on genotype, demonstrating how large-scale genetic studies translate into personalized dietary recommendations. Immunotherapy–nutrition interactions represent an emerging area of precision application. Studies in melanoma and lung cancer patients focus on fatty acid metabolism genes (FASN, FADS1/2), with omega-3 fatty acid supplementation and fiber intake optimization based on genetic variants enhancing the efficacy of immune checkpoint inhibitors. These findings support the integration of precision nutrition with immunotherapy protocols.

Advanced machine learning models integrate clinical, microbiome, and dietary data for treatment selection with impressive accuracy. Autonomous AI agents achieve 87.5% accuracy in using appropriate clinical tools for oncology decision-making, while neural network models predict disease risk from 168 circulating metabolic markers in large population studies (214). The Food4Me European study extension demonstrates practical AI implementation, involving 1,607 participants across seven countries with genetic testing for FTO, APOE, MTHFR, and TCF7L2 variants (218). Genotype-based recommendations resulted in 1.5–2 times greater dietary behavior changes compared to general advice, validating the clinical utility of AI-driven personalized nutrition. Real-time biomarker monitoring through wearable devices enables continuous optimization of interventions. Kaiku Health's platform serves over 64,000 patients across more than 40 European cancer clinics, achieving patient recommendation rates of 95–99% and improved care perception of 86–90%. The platform's machine learning algorithms predict symptom onset and progression while reducing the healthcare system's phone call burden by 57%.

The primary barriers restricting bioactive compound absorption operate through interconnected mechanisms that significantly reduce therapeutic potential. Five critical limitations dominate across compound classes: extensive first-pass metabolism, poor solubility characteristics, gastrointestinal absorption barriers, chemical instability, and active efflux transport. First-pass metabolism presents the most significant barrier for most bioactive compounds. Polyphenols undergo rapid glucuronidation via UDP-glucuronosyltransferases (UGT1A1, UGT1A8, UGT1A9), with up to 95% of absorbed compounds being conjugated before reaching systemic circulation (219). This process occurs both in intestinal enterocytes and hepatic tissue, creating dual metabolic barriers (220). Recent studies demonstrate that men show four-fold higher UGT2B17 expression than women, explaining significant gender differences in bioavailability patterns (221).

Solubility limitations create dissolution rate bottlenecks that constrain absorption. Most polyphenol aglycones exhibit water solubility below 20 μg/mL (222), while carotenoids require micellization with dietary fats for absorption, showing three- to five-fold higher bioavailability when consumed with fatty meals (223). Phytosterols face dual solubility challenges, being poorly soluble in both water and oils despite structural similarities to cholesterol, which achieves 56% absorption compared to phytosterols' 0.5–2% (224). Gastrointestinal absorption barriers include limitations of tight junctions, diffusion constraints of the mucus layer, and pH-dependent degradation. The colon mucus layer reaches a thickness of 830 μm, creating significant diffusion barriers for large molecules. Additionally, anthocyanins demonstrate particular instability at neutral pH, losing both color and bioactivity through rapid degradation mechanisms. Efflux pump interactions, particularly through P-glycoprotein (ABCB1/MDR1), actively limit compound absorption by recognizing a wide range of hydrophobic bioactive substances and using ATP-dependent transport to expel them from enterocytes back into the intestinal lumen. ABCG5/G8 transporters specifically target phytosterols, explaining their extremely low bioavailability despite their structural similarity to readily absorbed cholesterol (225). Genetic polymorphisms, particularly rs1045642 (3435T>C), significantly affect pump activity, with TT genotypes showing higher extrusion capacity.

Nanodelivery systems address bioavailability limitations through sophisticated mechanisms that enhance solubility, protect compounds from degradation, improve intestinal absorption, and bypass first-pass metabolism (226). Four primary technologies dominate current applications: liposomes, nanoparticles, nano-emulsions, and emerging nanovesicular systems. Liposomes provide versatile encapsulation platforms through phospholipid vesicles that accommodate both hydrophilic and lipophilic compounds. Recent advances include enhanced PEGylation strategies for improved circulation time, stimuli-responsive systems for targeted release, and novel surface modifications using ligand conjugation for active targeting. Encapsulation occurs through passive loading during formation, active loading using pH gradients, or direct lipid bilayer integration for lipophilic compounds. The enhanced permeation and retention (EPR) effect enables passive targeting through leaky vasculature, while active targeting utilizes antibody or peptide recognition systems.

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) offer controlled release capabilities with superior stability profiles. SLNs utilize solid lipid cores stabilized by surfactants, achieving 28–81% encapsulation efficiency for compounds like curcumin. NLCs improve upon SLN technology by incorporating liquid lipids that create imperfect crystal structures, enabling higher drug loading capacity and reduced compound expulsion during storage. Recent innovations include supercritical fluid production methods and hybrid polymer–lipid systems that combine the benefits of both platforms. Nano-emulsions deliver exceptional stability and enhance bioavailability through systems typically ranging from 10 to 100 nm in particle size (227). Oil-in-water formulations dominate food applications, while Pickering emulsions utilize solid particle stabilization for enhanced stability (228). Recent formulation advances include OSA-modified starch as novel emulsifiers and ultrasonic-assisted formation techniques that increase encapsulation efficiency by 15–20%. These systems enhance bioavailability through multiple mechanisms: particle size reduction increases surface area-to-volume ratios, amorphous state formation prevents crystallization, and surface modification improves wettability.

Protection from degradation occurs through physical barrier effects, antioxidant co-incorporation, controlled microenvironment maintenance, and thermal stability during processing (229). Improved intestinal absorption results from enhanced permeation through tight junction modulation, lymphatic targeting via lipid-based systems, receptor-mediated endocytosis, and size-dependent paracellular transport. Bypassing first-pass metabolism utilizes lymphatic delivery for direct access to systemic circulation, targeted release for site-specific delivery, and sustained release to reduce metabolic clearance.

Eutectic systems and co-crystal technologies provide alternative approaches for bioavailability enhancement through molecular-level modifications that improve solubility, stability, and dissolution characteristics (230). Deep eutectic solvents (DES) have emerged as particularly promising platforms, formed by combining hydrogen bond acceptors with donors at specific molar ratios to create green, sustainable formulation systems (231). DES enhance bioavailability through sophisticated molecular mechanisms. Extensive hydrogen bonding networks solubilize hydrophobic bioactive compounds through multiple interaction types, including ionic, hydrogen bonding, and van der Waals forces (232). Polarity modulation allows for adjustments in the HBA/HBD ratio and water content to match specific compound requirements (233). Matrix stabilization maintains amorphous forms to prevent crystallization, while permeability enhancement occurs through membrane fluidity modulation.

Recent applications demonstrate remarkable effectiveness across compound classes. Choline chloride-based DES systems achieve two-fold higher quercetin extraction yields compared to conventional solvents. Hydrophobic DES using DL-Menthol and camphor reached 163.5 ± 1.1 mg/100 g carotenoid extraction from orange peels (234). β-Carotene encapsulation in whey protein concentrate using choline chloride-butanediol DES achieved optimal loading capacity, while astaxanthin ester solubility reached 473.63 mg/mL in DES-based microemulsions (234). Co-crystal technologies utilize multi-component crystalline materials formed through non-covalent interactions between bioactive compounds and Generally Recognized as Safe (GRAS) co-formers (235). Formation occurs through hydrogen bonding, π-π stacking interactions, van der Waals forces, and halogen bonding. These systems enhance bioavailability through solubility modulation, supersaturation generation via “spring and parachute” effects, simultaneous improvements in solubility and permeability, and protection of chemical stability (236).

Recent quercetin co-crystal developments include four new systems: quercetin:caffeine, quercetin:caffeine:methanol, quercetin:isonicotinamide, and quercetin:theobromine dihydrate, each demonstrating superior pharmacokinetic properties (237). Machine learning approaches now enable the prediction of flavonoid co-crystal formation, while production using food-grade co-formers has expanded significantly. Solid dispersions represent advanced fourth-generation systems that incorporate both solubility enhancement and controlled release properties. Novel preparation methods include hot melt extrusion with improved parameters, spray drying with optimized carriers, supercritical anti-solvent processes, and electrospraying using DES solvents. Combination carriers like HPMC 4000 with PEG 6000 provide swelling-based dissolution enhancement, while surface-active carriers, including Gelucires and Poloxamers, improve performance characteristics (238) (Table 3).

Emerging evidence reveals significant population-specific toxicity risks for several widely consumed functional food ingredients, with genetic factors, smoking status, and concurrent medications dramatically altering safety profiles (239). Critical safety thresholds have been established for compounds like EGCG (800 mg/day limit) (240) and β-carotene (contraindicated in smokers), while hepatotoxicity cases linked to curcumin formulations have prompted regulatory warnings across multiple jurisdictions. The landscape of functional food ingredient safety has shifted substantially, with precision medicine approaches now essential for risk assessment. Notable developments include identification of HLA-B35:01 genetic susceptibility for hepatotoxicity (241), establishment of regulatory limits based on pharmacogenetic data, and documentation of serious adverse drug–nutrient interactions in vulnerable populations. These findings challenge the traditional “natural equals safe” paradigm and necessitate evidence-based dosing recommendations.

The European Union has implemented the most comprehensive regulatory framework for functional food ingredients. Commission Regulation EC 2023/2006 establishes mandatory Good Manufacturing Practice requirements for food contact materials, while updated EFSA tolerance frameworks provide systematic approaches to determining upper intake levels. EFSA scientific opinions from 2022 to 2025 have established ADI values for multiple compounds: curcumin (3 mg/kg body weight) (243), resveratrol (150 mg/day maximum), and tetrahydrocurcuminoids (2 mg/kg body weight). These assessments incorporated margin of exposure calculations that consider vulnerable populations, particularly pregnant women and children. Harmonized labeling requirements now mandate warnings for EGCG-containing products, including contraindications for pregnancy, lactation, children under 18, and fasting consumption. These evidence-based warnings represent a paradigm shift toward population-specific safety communication.

The FDA has expanded qualified health claims for omega-3 fatty acids related to hypertension and coronary heart disease risk reduction while maintaining GRAS status for most functional ingredients (243). However, warning letters continue to be issued for unauthorized disease claims, particularly for curcumin-based products. Small Entity Compliance Guides provide enhanced clarity for omega-3 nutrient content claims, while discussions on modernizing 21 CFR Part 111 dietary supplement regulations are ongoing. The FDA has not established specific maximum daily intake limits for most compounds, relying instead on GRAS provisions and post-market surveillance. Health Canada's Supplemented Foods Regulations entered a transition phase through December 2025, requiring premarket assessment for novel ingredients. The TMAL system phase-out signifies a move toward more rigorous safety evaluation protocols. FSANZ updated dietary exposure assessment principles in 2024, emphasizing the integration of food chemical concentration and consumption data for regulatory decision-making. These frameworks enable more sophisticated risk assessments that incorporate population-specific consumption patterns.

The potential of functional food active ingredients in combating conditions such as cancer has received widespread attention at the in vitro and animal levels, but high-quality human evidence is relatively scarce. Many studies remain at the stage of small-sample clinical trials or observational studies, and there is a lack of rigorous large-scale RCTs to validate their efficacy. In the case of curcumin, for example, although basic research has been fruitful, clinical trial results have not been adequately followed up. A review investigated curcumin-related studies in the ClinicalTrials database and found that < 10% of the nearly 300 clinical studies registered had published results, and these trials generally suffered from small sample sizes, a single disease type, and inconsistent intervention protocols. More importantly, few studies published results, meaning that many trials failed to produce clear conclusions (249). Overall, there is still a lack of convincing evidence for the clinical efficacy of functional food actives, and large-scale, high-quality RCTs are urgently needed to facilitate the translation of these actives from the laboratory to clinical applications.

Functional foods and dietary supplements are regulated differently across countries and regions, which significantly impacts their marketability and clinical application. Inconsistency in regulatory frameworks and the lack of standards may result in uneven product quality and exaggerated claims. In the United States, such products are categorized as dietary supplements and are not subject to the same rigorous validation of efficacy as drugs, with regulation focusing on safety rather than efficacy. This relatively lax regulatory framework has facilitated commercialization but also raised quality concerns (250). On the contrary, Japan, Korea, and other countries have established specialized approval systems for functional foods (e.g., FOSHU certification for “Foods for Specific Health Uses”), requiring the submission of sufficient scientific evidence to support health claims and implementing strict controls before and after marketing. The European Union has also formulated guidelines for the safety assessment of plant extracts as food additives and audited the functional claims, raising the threshold for market entry while ensuring safety (251). As regulations and standards vary from country to country, companies face approval and compliance challenges when promoting such products in different markets. A survey found that about 59% of curcumin supplements marketed in the U.S. did not meet active ingredient content standards, and many contained residual solvents, reflecting the difficulty of maintaining consistent product quality under the current regulatory system. Therefore, to promote the clinical translation of functional food active ingredients, not only is more scientific evidence needed to support their efficacy, but there is also a call for unified standardized quality standards and regulatory policies to ensure safety and effectiveness while accelerating product compliance in the market.

Functional food active ingredients often suffer from poor water solubility, easy degradation, and low bioavailability. In recent years, nanotechnology has provided new methods for their delivery. By constructing nanocarriers, active ingredients can be protected from damage in the digestive tract environment, reducing toxicity and increasing their absorption rate in the gastrointestinal tract, thus significantly improving bioavailability. Some studies have encapsulated phenolic antioxidants in nanoliposomes, which not only effectively maintain the stability of the active ingredients but also improve their bioavailability (252). Similarly, the delivery of unstable nutrients using nanostructured carriers has yielded good results in enhancing their stability in food systems and extending shelf life (253). Notably, novel materials such as plant proteins are also being used as nanocarriers to develop edible and safe delivery systems. However, there are still concerns about the large-scale application of nanodelivery in food, as the long-term safety of nanomaterials in vivo remains unclear (254). Future research needs to focus on the safety assessment and biocompatibility improvement of nanocarriers to ensure that efficacy is enhanced without introducing new safety risks.

Delivering functional food active ingredients together with traditional chemotherapeutic drugs via nanocarriers is another innovative strategy to improve anticancer efficacy. Studies have demonstrated that the combination of natural products and chemotherapeutic drugs can exert synergistic antitumor effects through multiple mechanisms: in addition to directly inhibiting tumor cell proliferation and inducing apoptosis, it can also overcome multidrug resistance (MDR) and reduce the toxic side effects of chemotherapy. Nanodelivery co-delivery system (NDCDS) allows two active substances to be encapsulated in the same nanocarrier, delivered simultaneously to the tumor site, and released in a designed ratio and time sequence, resulting in synergistic effects within the tumor cells (255). Co-loading plant anticancer components such as quercetin and curcumin with multiple chemotherapeutic agents in nanocarriers significantly enhanced apoptosis induction and proliferation inhibition of tumor cells. This type of nano-co-delivery strategy has demonstrated superior anticancer activity over single drugs in vitro and in animal models. Looking forward, combined nanodelivery of functional food active ingredients with chemotherapeutic agents is considered a promising anticancer modality that can simultaneously improve efficacy and reduce the occurrence of drug resistance and toxicity. According to the review, nano-co-delivery of natural products with chemotherapeutic agents is expected to be the basis of new tumor therapeutic strategies that facilitate the development and translation of anticancer drugs (256). Although currently mostly in preclinical studies, this co-delivery strategy is expected to gradually move toward clinical application as delivery systems improve and more pharmacokinetic/toxicological data accumulate (Table 4).

To move from experimental research to the clinical application of functional food active ingredients, close collaboration among the fields of biomedicine, food science, nutrition, pharmacology, and nanotechnology is essential. In fact, the concept of functional food itself is a product of multidisciplinary intersection, integrating the principles of food science, nutrition, and pharmacology to achieve comprehensive health interventions. In future development, interdisciplinary teams can showcase their respective strengths: food science and nanotechnology can provide new carriers and preparation processes to enhance the stability and targeting of the active ingredients; biomedical research can elucidate the molecular mechanisms of action of the active ingredients and their targets; and nutrition and clinical medicine can translate these findings into implementable dietary recommendations or complementary therapeutic programs, which can then be verified in clinical trials. This kind of collaborative innovation “from lab to clinic” will effectively promote the transformation of functional foods into medicinal value. A typical example is the recently proposed concept of “Dietary Oncopharmacognosy”, which integrates resources and methods from natural product chemistry, drug discovery, big data, and nutritional sciences, utilizing multiple sources such as natural product databases, anticancer drug databases, and food histology. The strategy combines resources and methods from natural product databases, anticancer drug databases, and food genomics, using artificial intelligence to design individualized anticancer dietary patterns for clinical testing. Accordingly, the researchers constructed an “anticancer food atlas” to quantify the number of active anticancer molecules contained in each food, which can be used to formulate precise nutritional programs for cancer patients (257). This novel interdisciplinary practice demonstrates that it is possible to make the active ingredients in functional foods into “edible anticancer prescriptions” and accelerate their clinical application through collaboration across different fields.

The active ingredients of functional foods are not only used for dietary interventions but also hold great potential to become lead compounds for new drugs. In the history of anticancer drug development, many landmark drugs (e.g., vincristine, paclitaxel, and artemisinin) were derived from natural products such as plants. This suggests that bioactive molecules from food may be transformed into effective anticancer drugs through established drug development pathways. In recent years, with advances in computational biology and medicinal chemistry, researchers have begun using computational simulation, virtual screening, and artificial intelligence techniques to identify anticancer candidates from natural products (258). These technologies can accelerate the identification of functional food ingredients with pharmacological activity and optimize their structures to enhance activity or reduce toxicity. Through molecular docking and machine learning model screening, new molecules with promising anticancer properties have been identified from natural compounds and validated for activity in cellular and animal models (258). Some functional ingredients have also been used as drug carriers or adjuvants to enhance the efficacy of existing anticancer drugs or mitigate their side effects, further expanding the role of functional food ingredients in the drug system. In summary, multidisciplinary collaboration not only promotes the clinical application of functional food active ingredients but also provides a steady stream of ideas and resources for new drug development. It is foreseeable that more active molecules derived from natural diets will emerge in future drug development pipelines, enriching our stockpile of anticancer weapons.