Polysaccharides are macromolecules with broad biological activities, widely present in nature, and play vital physiological roles (Chakka and Zhou, 2020). In recent decades, polysaccharides isolated from various medicinal herbs have gained significant attention due to their notable bioactivities. These include anti-inflammatory (Chen G. et al., 2023), gut microbiota regulation (Wang H. et al., 2024), anti-tumor (Ju et al., 2024), antioxidant (Liu X. et al., 2025), anti-diabetic (Bo et al., 2024), and immunomodulatory effects (Tang J. et al., 2024). By inhibiting the proliferation of LC cells, natural polysaccharides can effectively restrain the disease progression. Furthermore, the modulation of gut microbiota and the amplification of immune responses contribute to the enhancement of the efficacy of conventional LC treatments (Tian et al., 2024). Overall, polysaccharides demonstrate considerable potential in LC research, offering promising avenues for developing novel clinical interventions.

The polysaccharides derived from Laminaria japonica (Kunbu in Chinese) serve as key active components, with research by Jin W. et al. (2025) demonstrating their significant inhibition of viability, migration, and invasion in LC cells. These effects are mediated via regulating the PPARG pathway, where PPARG modulates PTGS2 to reduce inflammatory mediators and suppressing the AGE-RAGE axis, where AGE-RAGE regulates HIF-1α to block angiogenesis, as identified by network pharmacology. Key downstream targets CASP3, BCL2 and CCND1 are modulated, with the S-C fraction stabilizing PPARG and interfering with CASP3 activation to balance cell apoptosis and survival. This molecular cascade from Laminaria japonica polysaccharides to core targets and oncogenic pathways supports their adjunctive potential in NSCLC by inhibiting cancer cell proliferation, migration, and metastasis. Although network pharmacology provides a systematic hypothetical framework for the mechanism of action of laminarin, these predicted targets and pathways still require validation through more direct molecular biology experiments, such as siRNA-mediated knockdown of key targets, to establish definitive causal relationships. Houttuynia cordata Thunb. Contains various bioactive compounds, among which polysaccharide HCA4S1 has shown particular relevance for LC by upregulating cleaved caspase-3 and cyclin B1 expression, suggesting induction of cell cycle arrest and apoptosis in A549 cells (Han et al., 2018). Additionally, polysaccharide Suc40 extracted from Poria cocos (Schw.) Wolf (Fuling in Chinese) exhibits both anti-inflammatory and anti-cancer properties, inhibiting IL-6 and TNF-α while suppressing AKT/p38 signaling pathways, and exerting anti-proliferative effects against NSCLC cells via activation of caspase-3/7/8/9-mediated apoptosis (Qiu et al., 2024). Similarly, network pharmacology studies have identified that GQZ lipopolysaccharide (Lycium barbarum L.) targets NSCLC primarily through lipopolysaccharide-related mechanisms and suppression of the PI3K/AKT1 pathway, thereby inhibiting proliferation via downregulation of C-MYC and PCNA and inducing apoptosis through modulation of BCL2/BAX ratio and caspase activation, as demonstrated in both in vitro and in vivo models (Zhang et al., 2022).

Collectively, these polysaccharides of medicinal and edible substances exert anti-lung cancer effects not through single-target actions but via multi-target mechanisms that simultaneously engage tumor cells, immune regulation, and the systemic microenvironment, forming an integrated therapeutic network.

Polyphenolic compounds are plant-derived secondary metabolites characterized by benzene rings with multiple phenolic hydroxyl groups. They are abundantly present in common dietary sources such as fruits, vegetables, and grains, as well as in various medicinal and edible substances (Fu et al., 2024). Studies have confirmed that these compounds demonstrate a range of biological properties, including sleep regulation (Pérez-Jiménez et al., 2023), modulation of gut microbiota (Rodríguez-Daza and de Vos, 2022), anti-inflammatory (Zamani-Garmsiri et al., 2022), antioxidant (Zhong et al., 2025), antibacterial (Turuvekere Vittala Murthy et al., 2021), and immunomodulatory effects in oncology (Wang Q. et al., 2022). Through these synergistic interactions, polyphenolic compounds exert a significant influence in the field of LC research.

Curcumin, the primary active constituent of turmeric (Curcuma longa L.), represents an extensively studied natural compound with significant therapeutic potential, predominantly attributed to its polyphenolic nature. Research by Cho et al. (2024) confirmed that curcumin exhibits notable anti-cancer activity, particularly when synergized with piperine from black pepper. This observed synergy underscores the importance of investigating medicinal and edible substances combinations through a multi-target perspective, as advocated by network pharmacology. Polyphenols isolated from Lonicera japonica Thunb. demonstrate substantial anti-lung cancer properties by modulating mitochondrial-dependent apoptotic pathways in A549 cells, characterized by AKT dephosphorylation-induced Bax/Bcl-xL ratio increase, leading to caspase-9-mediated caspase-3 activation and PARP cleavage (Park et al., 2017). Similarly, cannabidiol derived from Cannabis sativa L., especially cannabidiol (CBD), suppresses viability and invasion in A549 and H460 LC lines in a CB1/CB2/TRPV1-dependent manner while reducing PAI-1 expression and inducing apoptosis via upregulation of COX-2 and PPAR-γ (Nigro et al., 2021; Ramer et al., 2010). Furthermore, eugenol, which mediates its effects on LC by targeting β-catenin to inhibit its nuclear transport, induce cytoplasmic degradation via N-terminal Ser37 phosphorylation, downregulatees CSC markers, enhances apoptosis, and suppresses cell proliferation (Choudhury et al., 2021).

Together, these polyphenolic compounds act through common mechanisms against LC, ranging from apoptosis induction and proliferation suppression to signaling pathway modulation, likely due to their phenolic hydroxyl groups that facilitate interactions with key biological macromolecules.

Flavonoids are a class of phytochemicals with diverse biological activities that contribute significantly to human health. They can effectively neutralize free radicals, making them valuable in supporting the management of various diseases. Moreover, they find extensive applications in nutraceuticals, cosmeceuticals, and pharmaceuticals (Billowria et al., 2024; Mohan et al., 2025). These compounds interact with multiple biological targets, exhibiting a range of effects including anti-inflammatory (Wang et al., 2021), antioxidant, antibacterial (Jomova et al., 2025), and notably anti-cancer properties (Jeong et al., 2023). Research indicates that flavonoids play an important role in influencing the progression of LC.

Research demonstrates that flavonoids significantly influence LC progression. Nelumbo nucifera Gaertn. flavonoids (LLF) induce apoptosis in A549 and H446 cells by initiating intracellular reactive oxygen species (ROS) burst, which in turn activates the p38 MAPK pathway. The activated p-p38 MAPK promotes the mitochondrial apoptotic pathway, evidenced by an increased Bax/Bcl-2 ratio, cytochrome c release, and subsequent activation of the caspase-9/3 cascade (Jia et al., 2021). Similarly, puerarin 6″-O-xyloside (PXY) suppresses the self-renewal and invasion capabilities of LC stem-like cells by inhibiting Akt/c-Myc signaling activation, thereby downregulating stem cell markers CD44, CD133, and ALDH1 (Tao et al., 2020). Components like quercetin and kaempferol regulate apoptotic factors, downregulate Bcl-2, upregulate Bax, activate caspase-3/9 to induce cancer cell apoptosis. Their activity is mediated through the inhibition of upstream pathways, including quercetin’s suppression of the PI3K/Akt/mTOR axis and genistein’s inhibition of ERK1/2 and PI3K/Akt, which collectively reduce VEGF signaling and suppress cancer stem cell characteristics. Additionally, genistein promotes autophagy via Bcl-xL/Beclin-1 dissociation, underscoring a multi-targeted mechanism (Khazdair et al., 2021). In particular, quercetin is frequently identified in network pharmacology studies as a key hub node, capable of simultaneously interacting with multiple targets across different pathways, which exemplifies the network-based polypharmacology of flavonoids. It should be noted that the multi-target modulatory effects of quercetin on the PI3K/Akt and autophagy pathways observed in vitro were predominantly achieved at relatively high concentrations. Whether equivalent effective concentrations can be attained in vivo, and whether such multi-target engagement may lead to off-target toxicity in normal cells, remain subjects requiring further investigation. Furthermore, linarin from Chrysanthemum × morifolium (Ramat.) Hemsl. suppresses radiation-induced cell migration and invasion in A549 cells through the inhibition of IKK-mediated IκB-α phosphorylation, which prevents NF-κB nuclear translocation, leading to the downregulation of MMP-9 expression, thereby inhibiting cancer invasion (Jung et al., 2019).

Through the coordinated regulation of key protease systems and signaling networks, these flavonoids disrupt pivotal pathways such as p38 MAPK, Akt/c-Myc, and NF-κB. This multi-target mechanism, often revealed by network pharmacology predictions, underpins their broad chemopreventive potential across the pathogenesis of LC, which includes inducing apoptosis, suppressing stemness, and limiting metastasis.

Terpenoids are important naturally occurring bioactive substances widely found in plants and fungi. They have been demonstrated to have marked therapeutic efficacy, contributing to lowering blood glucose (Wang M. et al., 2024) and protecting liver function (Hao et al., 2024), alongside possessing anti-inflammatory (Chen J. J. et al., 2023), antioxidant (Huang et al., 2022), anti-fatigue (Zhang Y. et al., 2024), antiviral (Wimmerová et al., 2023), and crucially anticancer properties (Aly et al., 2024). Research has identified terpenoids as multi-target plant metabolites that can effectively inhibit tumor cell proliferation, migration, and invasion. They represent one of the most significant sources of bioactive compounds capable of suppressing LC progression (Markov et al., 2017).

Because of the diverse mechanisms of terpenoids, these compounds demonstrate significant potential in LC management. β-sitosterol from Raphanus sativus L. sprouts inhibits miR-181a-3p to upregulate the expression of its downstream target SHQ1, activates the SHQ1/UPR signaling pathway, and thereby promotes apoptosis and suppresses proliferation of LC cells. This intricate microRNA-mRNA-pathway cascade highlights the multi-layered regulatory networks that can be deciphered through integrated pharmacological approaches (Wang H. et al., 2024). Glycyrrhetinic acid (GA), a primary bioactive constituent of licorice (Glycyrrhiza uralensis Fisch.). Guo et al. (2024) employed an integrated strategy combining activity-based protein profiling with proteomics and histopathological validation to investigate the potential targets of GA against NSCLC, providing a multi-dimensional view of its mechanism. In vitro and in vivo results indicated GA significantly inhibited NSCLC via promotion of peroxiredoxin-6 and caspase-3-mediated mitochondrial apoptosis. Chen et al. (2015) conducted a study investigating that crocin from Crocus sativus L. suppresses proliferation in A549 and SPC-A1 cells in a dose-dependent manner, accompanied by increased p53 and decreased Bcl-2 mRNA levels, leading to apoptosis. Additionally, maslinic acid promotes apoptosis in A549 cells by modulating IAP family proteins (Bai et al., 2016; Yu et al., 2021), and the extract from Cornus officinalis Siebold & Zucc. shows inhibitory activity against A-549 LC cells (Li et al., 2015).

Collectively, terpenoids achieve multi-target suppression of LC proliferation by coordinately inducing apoptosis, arresting the cell cycle at G0/G1 phase, and regulating core signaling pathways including p53 and PI3K/Akt.

Saponins are a diverse group of compounds widely distributed in the plant kingdom, characterized by their amphiphilic nature resulting from a hydrophobic aglycone linked to hydrophilic sugar chains via glycosidic bonds (Güçlü-Ustündağ and Mazza, 2007; Liu H. et al., 2025). Studies indicate that saponins demonstrate anti-tumor efficacy across various cancer types, including breast cancer (Wu et al., 2025), colorectal cancer (Bai et al., 2025), and osteosarcoma (Jin K. et al., 2025). Recent studies have revealed that saponins derived from medicinal and edible substances also demonstrate promising bioactivity in LC management, showing potential for therapeutic application.

Saponins exhibit multi-target anti-lung cancer effects through coordinated mechanisms. Lily saponin, in addition to its significant anti-hepatocellular carcinoma effects (He et al., 2024). It also has been demonstrated to have potential effects on human LC cell proliferation, apoptosis, migration, and invasion. For example, steroidal glycoside six can exhibit potent cytotoxicity against the A549 lung cancer cell line, with a half-maximal inhibitory concentration of 1.49 μM (Zhou et al., 2024; Luo et al., 2018). Furostanol saponin, a novel compound isolated from Asparagu cochinchinensis (Lour.) Merr., significantly inhibits H1299 LC cell proliferation and induces apoptosis, by doing so, it slows disease progression (Zhang R.S. et al., 2021). This anti-lung cancer activity of steroidal saponins provides a modern research example of TCM against tumors. Furthermore, studies have identified two new furostanol saponins, macrostemonoside E and F, as key active components responsible for the anti-lung cancer activity in Allium chinense G.Don (Wang Y. et al., 2019). Ophiopogonin B has been shown to inhibit cell viability and proliferation, consequently suppressing invasion and migration in NSCLC cell lines through mechanisms associated with epithelial-mesenchymal transition (EMT) (Zhang S. et al., 2021). A recent study by Feng L. et al. (2024) confirmed that ginsenoside Rb1 induces LC cell apoptosis by altering protein levels and activating the external apoptotic pathway. Additionally, Jujuboside B triggers endoplasmic reticulum stress, leading to the activation of the PERK-eIF2α-ATF4 signaling axis. This cascade results in the upregulation of ATF3, which subsequently suppresses the expression of SLC7A11. The downregulation of SLC7A11 depletes glutathione and inactivates Gpx4, culminating in lethal lipid peroxidation and ferroptosis (Kim and Ko, 2025). These saponins collectively exert multi-target anti-tumor effects by synergistically regulating the Bcl-2/Bax ratio, activating the caspase cascade to induce apoptosis, while simultaneously inhibiting EMT and matrix metalloproteinase (MMP) activity, which in turn suppresses LC cell proliferation, migration, and invasion.

Together, these saponins exert their anti-tumor effects by coordinately regulating the Bcl-2/Bax ratio, activating caspase cascades to induce apoptosis, while simultaneously inhibiting EMT and MMPs activity, thereby ultimately suppressing LC cell proliferation, migration, and invasion.

Bioactive components encompass a diverse range beyond the previously mentioned polysaccharides, flavonoids, polyphenols, terpenoids, and saponins. Other notable constituents include lectins, lipids, and alkaloids. Various bioactive components from medicinal and edible substances demonstrate anti-lung cancer effects through distinct mechanisms. Seabuckthorn Pulp Oil combined with DTX showed synergistic anti-cancer activity through caspase-independent autophagy and senescence induction, accompanied by increased ROS production, LC3 protein expression, G1 phase arrest, and enhanced senescence-associated β-galactosidase activity (Batbold and Liu, 2022). Polygonatum cyrtonema lectin induces significant anti-tumor effects through cell death and autophagy, with ROS scavenger NAC inhibiting PCL-induced cell death and autophagy in A549 cells (Liu et al., 2016). Neferine, an alkaloid from N. nucifera Gaertn., induces apoptosis in NSCLC cells by elevating ROS and reducing the BCL2/BAX ratio. Simultaneously, it suppresses invasion and EMT by targeting ROCK1, inhibiting MLC phosphorylation, and reversing EMT markers. This dual action effectively blocks tumor growth and metastasis. (Hu et al., 2023). Cinnamon essential oil triggers cell death in LC cells by causing cell cycle arrest, increasing ROS accumulation, inducing mitochondrial depolarization, and elevating caspase-3, 8, and nine levels (Mohanty et al., 2024). Abeesh et al. (2021) demonstrated that sword bean extract inhibits cell growth, induces apoptosis, and significantly suppresses the development of mouse ascites and solid tumors. Echinacoside from Cistanche deserticola Ma induces pyroptosis in NSCLC cells through the mitochondrial-mediated Raf/MEK/ERK signaling pathway (Tang Y. et al., 2024). Coixol and a known compound isolated from coix bran show anti-proliferative effects against NSCLC cells (Lee et al., 2008; Wang L. H. et al., 2024).

In summary, medicinal and edible substances demonstrate unique advantages and potential in LC prevention and treatment through their rich bioactive components and multi-component, multi-target synergistic mechanisms. Therefore, future research should focus on elucidating the multi-target synergistic mechanisms of active ingredients such as polysaccharides, polyphenols, and flavonoids in medicinal and edible substances, along with their specific molecular mechanisms in intervening key LC signaling pathways.

Inflammation represents the body’s normal immune response to invasive pathogens. Chronic inflammation is involved in multiple stages of cancer progression, including tumor initiation, cellular transformation, invasion, angiogenesis, proliferation, and metastasis (Zhao et al., 2021). Research indicates that chronic inflammation, which often accompanies and stimulates cancer development, contributes significantly to the high mortality rate in LC. Key mediators such as NF-κB, transcription activators, signal transducers, and hypoxia-inducible factors serve to bridge inflammation and cancer. Furthermore, driven by these complex factors, the inflammatory microenvironment promotes LC development through mechanisms such as inducing EMT in tumor cells (Odarenko et al., 2023). Various medicinal and edible substances, including flavonoids and polyphenols, exert influence on LC progression through their anti-inflammatory properties.

Anethole and shikimic acid, polyphenolic compounds derived from Illicium verum Hook. f., have been reported through multiple mechanisms, including anti-inflammatory and antioxidant activities, to prevent and treat LC. Their anti-inflammatory effects are primarily demonstrated by inhibiting the NF-κB pathway to downregulate downstream TNF-α and fibronectin, and suppress oxidative stress-induced p53 overexpression. Meanwhile, they scavenge ROS, reduce MDA levels, and alleviate lung cell oxidative damage, disrupting the inflammatory-oxidative loop in TME to hinder LC progression (Abdelaziz et al., 2024). Menthol, a terpenoid from Mentha haplocalyx Briq. (Bohe in Chinese), exhibits anticancer activity against various human cancers including LC via regulating MAPK and PI3K/Akt pathways, inducing cell death, inhibiting invasion and migration, causing cell cycle arrest, upregulating Bax and p53 genes, and remodeling the chronic inflammatory microenvironment by modulating inflammatory mediators like TNF, IL-6, IFN-γ, and IL-8 (Tafrihi et al., 2021). Catalpol, a terpenoid from Rehmannia glutinosa (Gaertn.) Libosch. ex DC., significantly inhibits TGF-β1-induced migration and invasion in A549 cells through blocking Smad2/3 and NF-κB signaling activation, leading to suppression of inflammation-driven LC progression (Wang Z. et al., 2019; Laurindo et al., 2025). Similarly, amygdalin (Lin et al., 2022) and Polygonatum odoratum lectin (Li et al., 2014) also inhibit LC development through NF-κB pathway-mediated anti-inflammatory mechanisms. Dioscin, a natural saponin, reduces LC cell proliferation, invasion, and migration by decreasing p-AKT, MMP2, and PCNA expression, consequently inhibiting lung nodule formation, lung injury, and mortality in mouse models (Xi et al., 2022). Perilla seed oil, rich in α-linolenic acid, exerts anti-inflammatory and antioxidant effects by reducing TNF-α-induced ROS, inhibiting JNK phosphorylation and FOXO1 expression to lower MnSOD levels for antioxidant effects. It also suppresses NF-κB activation, decreasing downstream pro-inflammatory mediators, including IL-1β, IL-6, IL-8, TNF-α, COX-2, in A549 cells. These upstream links involving ROS and JNK and downstream links extending to FOXO1, MnSOD, NF-κB, and various cytokines clarify its anti-inflammatory and antioxidant mechanisms. (Tantipaiboonwong et al., 2021). Piperlongumine, an alkaloid from Piper longum L., induces apoptosis and inhibits invasion and metastasis in LC cells, while significantly reducing tumor volume and M2 macrophage polarization through endoplasmic reticulum stress induction in co-culture systems (Zhou et al., 2025).

The above study reveals that medicinal and edible substances exert their effects by inhibiting classic inflammatory pathways such as JNK and NF-κB. However, the underlying mechanisms of chronic inflammation-induced carcinogenesis lie in its ability to induce sustained activation of a complex signaling network, driving malignant remodeling of tissue structure. This process shares common characteristics across multiple chronic inflammatory diseases. For example, in chronic rhinosinusitis, Staphylococcus aureus infection upregulates MUC13 and synergistically activates the MEK1/2 and WNT2B signaling axis, leading to persistent mucosal inflammation and abnormal tissue remodeling (Feng et al., 2025b). In the development of LC, a similar logic applies: chronic inflammatory signals in the tumor microenvironment such as TGF-β and TNF-α induce epithelial-mesenchymal transition, promote extracellular matrix degradation, and ultimately drive invasion and metastasis of cancer cells by activating evolutionarily conserved pathways including MAPK/ERK, the downstream of MEK, and Wnt/β-catenin.

It is worth emphasizing that the anti-inflammatory effects of medicinal and edible substances precisely target this integrated signaling network. For instance, Catalpol mentioned in this section can inhibit TGF-β1-induced migration and invasion of A549 cells by blocking Smad2/3 and NF-κB signaling; Curcumin and Anethole have also been widely reported to inhibit the Wnt/β-catenin pathway. These findings indicate that medicinal and edible substances not only suppress inflammatory factors as per traditional understanding but also reprogram the signaling landscape—by regulating core hub pathways such as MEK/ERK and Wnt, they block the malignant transformation process from inflammation to epithelial-mesenchymal transition and tissue remodeling at the upstream level, thereby intervening in the progression of LC at a deeper level.

Redox reactions regulate fundamental biochemical processes, including energy production, substance metabolism, respiration, detoxification, and signal transduction. Due to their sustained proliferation, tumor cells maintain heightened metabolic activity and generate elevated levels of ROS compared to normal cells (Hayashi et al., 2024). ROS, encompassing both free radicals and non-radical species, serve as central mediators of oxidative stress, damaging cellular components such as lipids, proteins, and DNA, while also disrupting pulmonary homeostasis to create a microenvironment conducive to tumor development (Pizzino et al., 2017; Smolarz et al., 2025). The initiation and progression of LC are directly linked to systemic redox imbalance (Jaruga et al., 1994; Zabłocka-Słowińska et al., 2018; Miao et al., 2022), making antioxidant intervention an important aspect of its prevention and treatment.

An in vitro study demonstrated that raspberry seed methanol extract selectively inhibits the growth of LC A-549 cells while remaining non-toxic to normal lung cells. This extract effectively scavenges hydroxyl and superoxide anion radicals closely associated with LC pathology, indicating its anti-cancer effect is linked to potent antioxidant properties (Simonovic et al., 2021). Longan Pericarp-derived Phenolics extract demonstrated free radical scavenging capacity against DPPH and hydroxyl radicals, along with ferrous ion chelating ability in antioxidant assays (Bai et al., 2019). Research by Srisomsap et al. (2024) found that mulberry leaves (Morus alba L.) contain various bioactive polyphenolic compounds, particularly chlorogenic acid (CGA), which selectively inhibits the growth of MCF-7 cells and exhibits effective free radical scavenging activity against DPPH radicals, thereby suppressing migration and invasion activities against A549 LC cells. Hesperidin downregulates MMPs expression and enhances antioxidant status to counter nicotine toxicity and inhibit smoking-induced LC. Its antioxidant capacity also suppresses tumor cell proliferation in benzopyrene-induced LC mouse models, while additionally inhibiting NSCLC cell proliferation and promoting cell death through the miR-132/ZEB2 signaling pathway (Balakrishnan and Menon, 2007; Kamaraj et al., 2009; Tan et al., 2020). Ononin, a flavonoid extracted from Astragalus mongholicus Bunge, binds to HIF-1α through hydrogen bonds with TYR-131, GLN-133, GLN-134 and hydrophobic interaction with LEU-172, and when combined with radiotherapy, it suppresses the HIF-1α to VEGF pathway overactivation. This regulatory process inhibits LC cell growth by reducing proliferation and induces apoptosis via increasing Bax expression, decreasing Bcl-2 expression and elevating Cleaved Caspase3 level in vitro. In vivo studies using mouse models show this combination reduces lung tumor size and proliferation, promotes cancer cell apoptosis, alleviates abnormal HIF-1α pathway activation, and protects liver function by maintaining albumin and alkaline phosphatase homeostasis (Zhang Y. M. et al., 2024). Purslane (Portulaca oleracea L.) and its main active components influence LC development through multiple mechanisms, including antioxidant effects, inhibition of tumor angiogenesis, and suppression of LC cell proliferation. Its seed oil, whole plant chloroform extract, and alkaloids concentration-dependently inhibit LC cell proliferation and reduce cell viability. Lee et al. (2021) confirmed that FDY2004, an anti-cancer herbal formulation composed of Moutan Cortex, Persicae Semen, and Rhei Radix et Rhizoma, affects LC through molecular mechanisms involving the regulation of cell proliferation and growth, cell survival and death, as well as oxidative stress responses.

The immune response plays a vital role in defending against external antigens while maintaining tolerance to self-antigens (Han et al., 2025). This balance, known as immune homeostasis, is essential for overall health. When tumor cells invade and proliferate, immune cells such as macrophages and T cells are activated by signaling molecules within TME, mounting a defensive response against LC cells. Consequently, immunomodulation plays a crucial role in influencing the progression and prognosis of LC.

CAVAPs from Citrus maxima (Burm.) Merr. exhibit multiple biological activities. They demonstrate significant DPPH free radical scavenging capacity in terms of antioxidant activity, and show cytotoxic effects against both human breast cancer MCF-7 cells and LC HCC827 cells. In Addition, they possess immunoenhancing properties. Research by Shen et al. (2017b) found that CAVAPs may activate macrophages through the MAPK and NF-κB signaling pathways. This is evidenced by the increased phosphorylation of ERK, JNK, p38 and p65 proteins, leading to the upregulated expression and secretion of key immune mediators including iNOS, TNF-α, IL-1β and IL-6. Similarly, another study revealed that CAVAPs exhibit stronger DPPH scavenging activity, FRAP, and reducing power, influencing LC mediated by antioxidant mechanisms (Shen et al., 2017a). These findings indicate CAVAPs can affect LC development through dual mechanisms of antioxidant activity and immunoregulation. 6-Gingerol, a bioactive polyphenolic compound extracted from fresh or dried ginger, demonstrates broad-spectrum anticancer activity. Kang et al. (2023) discovered that 6-gingerol inhibits LC cell proliferation and induces DNA damage response, cell cycle arrest, and apoptosis in NSCLC cells. Furthermore, iron metabolism enhances anticancer capacity by maintaining iron homeostasis through PD-L1/Akt/β-catenin/WIP signaling axis regulation. Specifically, PD-L1 activates PI3K/Akt to inhibit β-catenin degradation, promoting β-catenin binding to the WIP promoter and subsequent WIP transcription. This axis drives LC cell proliferation, migration, and invasion, while iron metabolism-mediated PD-L1 downregulation disrupts this pro-tumorigenic cascade. Additionally, 6-gingerol can modulate PD-L1 expression, playing a vital role in cancer immunotherapy (Yu et al., 2020). Kang et al. (2021) experimentally tested the effects of the total flavonoids from Taraxacum mongolicum Hand.-Mazz. on cancer cells in LC models, finding increased levels of CD4⁺, CD8⁺ T cells and CD4⁺/CD8⁺ ratio, elevated IL-2, IL-3, IFN-γ, and TNF-α levels, along with significantly decreased Ki67 expression, thus inhibiting LC cell proliferation and enhancing host immunity. Platycodin D, the main pharmacological component of Platycodon grandiflorus (Jacq.) A.DC., demonstrates various pharmacological activities through oxidative stress defense mechanisms. Studies have confirmed that Platycodin D exhibits potential anti-tumor, anti-cachexia, and immunomodulatory activities in athymic nude mice bearing lung H520 tumor cells (Park et al., 2014; Feng M. et al., 2024), likely combating LC exacerbation through immune enhancement. Moracin N (M. alba L. leaves) directly binds to the E158 residue of PD-L1, triggering PD-L1 tyrosine phosphorylation to promote its degradation. This binding disrupts the PD-L1/PD-1 interaction, reversing CD8⁺ T cell exhaustion by reducing CD8⁺PD-1⁺ subsets and enhancing CD8⁺GZMB⁺ cytotoxic T cell function. Together with synergistic effects from anti-PD-1 antibodies, MAN modulates the tumor immune microenvironment, ultimately suppressing LC tumorigenesis, progression, and metastasis (Ye et al., 2024).

In addition to the aforementioned strategies that directly target immune checkpoints or activate effector immune cells, intervening in the source of production of suppressive elements in the tumor immune microenvironment is another fundamental regulatory approach. Among these, Cellular Senescence and its accompanying senescence-associated secretory phenotype, a state characterized by the massive secretion of inflammatory factors, chemokines and proteases, has been identified as a key driver of shaping the immunosuppressive tumor immune microenvironment in recent years. Studies have confirmed that the abnormal expression of senescence-associated genes in tumor tissues is closely associated with poor prognosis. The underlying mechanism is that the inflammaging microenvironment created by senescent cells can directly induce T cell exhaustion and promote the infiltration of regulatory T cells, thereby facilitating tumor immune evasion, recurrence and metastasis. For instance, in head and neck squamous cell carcinoma, the specific expression profile of cellular senescence-related genes has been verified as an independent risk factor for predicting tumor recurrence and patient survival, which clearly reveals the causal link among senescence, immune dysregulation and tumor progression (Feng M. et al., 2025). Studies indicate that medicinal and edible substances can modulate cellular senescence-associated pathways, thereby ameliorating the tumor immune microenvironment and exerting potential effects in the prevention and treatment of LC. For example, Quercetin, as mentioned earlier, not only exhibits antioxidant properties and inhibits pro-cancer pathways such as PI3K/Akt, but also induces pro-apoptotic autophagy in LC cells via the SIRT1/AMPK signaling pathway. SIRT1 is a core molecule in the classical anti-aging pathway, and its activation can directly delay cellular senescence and reduce DNA damage. The upregulation of SIRT1 by Quercetin serves as the key link connecting “antioxidation-anti-aging-anti-lung cancer”at the molecular level. Consequently, medicinal and edible substances agents show promise in LC prevention and therapy by targeting senescence-associated signaling to favorably remodel the immunosuppressive tumor microenvironment.

Tumor angiogenesis refers to the formation of abnormal vascular networks within tumors, resulting from an imbalance between pro-angiogenic and anti-angiogenic signals (Alsaab et al., 2021). Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) play a central role in this process. The VEGF pathway, a key mediator of angiogenesis, has become an attractive target in multiple malignancies, including LC. Studies show that tumor angiogenesis not only supplies oxygen and nutrients required for LC cell proliferation but also establishes pathways that promote metastasis and create hypoxic regions, thereby contributing to drug resistance (Yan and Shi, 2024).

Ganoderma lucidum (Curtis) P. Karst. (Lingzhi in Chinese), a widely used medicinal food, demonstrates effective anti-tumor activity in EGFR-mutant NSCLC by downregulating EGFR expression through proteasomal and lysosomal degradation mediated by its bioactive components such as WSG and rLZ-8. Firstly, it suppresses cell survival and tumor progression by blocking the EGFR-mediated activation of the PI3K/Akt/mTOR and ERK/AP-1 cascades. Secondly, it attenuates the Wnt/β-catenin pathway through inhibition of LRP6 phosphorylation, thereby restraining EMT and angiogenesis. Additionally, it modulates the tumor microenvironment by activating M1 macrophages and NK cells while reducing immunosuppressive cytokines like IL-10 and TGF-β, thereby enhancing anti-tumor immunity and overcoming EGFR-TKI resistance (Zhang et al., 2025). Glycitin, a flavonoid extracted from Glycine max (L.) Merr. (Dandouchi in Chinese), shows potential for treating NSCLC. It exhibits significant anti-tumor activity by inhibiting tumor proliferation and metastasis through affecting the TOP2A protein function. A significant positive correlation exists between TOP2A expression levels and the expression of vasculogenic mimicry-related factors, suggesting that glycitin may exert therapeutic effects on NSCLC by targeting TOP2A and influencing its mediated cell proliferation and vasculogenic mimicry (Liu C. et al., 2025). Genipin from Gardenia jasminoides J.Ellis affects LC progression by directly suppressing the EGFR/JAK1/STAT3 signaling pathway. It binds to EGFR extracellular domain III to interfere with EGF binding and block EGFR phosphorylation then further inhibits downstream JAK1/STAT3 phosphorylation. This also modulates EMT-related proteins by upregulating E-cadherin and downregulating N-cadherin MMP9 Snail and RhoA. It induces G1/S phase arrest and apoptosis of LC cells and attenuates their migration and invasion a mechanism distinct from genipin’s UCP2-dependent regulation (Kim et al., 2025). A study conducted by Guo et al. (2025) has demonstrated that angelica sinensis extract by restoring blood component homeostasis, enhancing vascular structural integrity, accelerating blood circulation, promoting tumor vessel normalization, and blocking pro-angiogenic factor expression and receptor interactions improve tumor microenvironment hypoxia, inhibit aberrant angiogenesis, and delay progression from pulmonary nodules to LC. Han et al. (2016) found that Ginkgo biloba L. exocarp extracts influence LC development primarily by inhibiting tumor angiogenesis, as evidenced by reduced CD34 expression and suppressed microvessel density. They downregulate upstream Wnt3a to block β-catenin, further suppressing downstream VEGF and VEGFR2 transcription and subsequent AKT phosphorylation in LLC transplanted C57BL/6 mouse tumors. This Wnt/β-catenin-VEGF-VEGFR2-AKT pathway modulation is confirmed by dose-dependent inhibition of β-catenin, VEGF, VEGFR2, p-AKT/AKT protein expression and VEGF, VEGFR2 mRNA levels.

In summary, tumor angiogenesis serves as a critical process in LC tumor growth and metastatic dissemination, playing an important role in promoting LC cell metastasis, proliferation, and spread. Medicinal and edible substances represented by glycitin and genipin can influence LC progression by inhibiting angiogenesis. Therefore, the suppression of angiogenesis has been recognized as an attractive target for anti-lung cancer therapy.

Cellular regulation refers to the molecular mechanisms through which cells control their own proliferation, differentiation, apoptosis, and metabolism to maintain internal stability and normal physiological functions. When this regulation becomes dysregulated in cancer, cells gain the ability to proliferate indefinitely and evade cell death, leading to tumor development. Two critical aspects of this process are the evasion of apoptosis and the sustained activation of proliferation signals. Apoptosis, a classic programmed cell death mechanism, is normally initiated to eliminate damaged cells and maintain homeostasis in response to stimuli such as inflammation or oxidative stress (Mohammad et al., 2015; Vaghari-Tabari et al., 2021). Simultaneously, uncontrolled proliferation signals drive continuous tumor expansion. Therefore, restoring normal cellular control through the reactivation of apoptosis or suppression of proliferation constitutes a fundamental therapeutic approach in cancer management.

Phyllanthus emblica L. extract enhances its anti-lung cancer efficacy through green-synthesized iron oxide nanoparticles, where polyphenolic components stabilize particles via hydroxyl groups and generate reactive oxygen species that exacerbate DNA damage and promote cancer cell apoptosis, demonstrating superior performance compared to uncoated particles (Thoidingjam and Tiku, 2019). While this study employed advanced nanotechnology to enhance delivery efficiency, it simultaneously introduced new variables. The extent to which the observed potent anticancer efficacy is attributable to the medicinal and edible substances extract itself versus the nanocarrier requires discrimination through more rigorous controlled experiments. Sesamol, a polyphenolic lignan found in sesame seeds and oil, inhibits SK-LU-1 cell growth by increasing caspase-8, -9, and -3/7 activities, indicating apoptosis induction through both extrinsic and intrinsic pathways (Siriwarin and Weerapreeyakul, 2016). Additional polyphenolic compounds regulating LC cells include kaempferol from sand ginger (Zhang J. et al., 2023), myristicin from Myristica fragrans Houtt. (Maheswari et al., 2018), and compounds from Euryale ferox Salisb. (Nam et al., 2019). Quercetin, a natural flavonoid widely present in fruits and vegetables, inhibits cell viability and induces mitochondrial-dependent apoptosis in A549 and H1299 cells while promoting LC3-II and beclin-1 expression and suppressing p62, with autophagy inhibition effectively reducing quercetin-induced apoptosis (Guo et al., 2021). Mogrol, a terpenoid from Siraitia grosvenorii (Swingle) C.Jeffrey ex A.M.Lu & Zhi Y.Zhang, significantly suppresses proliferation and migration in multiple NSCLC cell lines (A549, H1299, H1975, SK-MES-1) and triggers excessive autophagy and autophagic flux leading to autophagic cell death (Li et al., 2022). Research by Imam et al. (2022) has shown that lactucin from Cichorium intybus L. inhibits lung adenocarcinoma cell proliferation without affecting normal lung cells, significantly arresting the cell cycle at G0/G1 phase and inducing apoptosis through downregulating the MAPK/ERK via reduced MEK/ERK phosphorylation to lower cyclin D1/CDK2/4 and upregulate p53-p21, arresting cell cycle at G0/G1. It induces apoptosis by p53-Bax upregulation and Bcl-2 suppression, and activates PTEN to inhibit Akt. Additionally, it binds PGM, PKM, LDHA and PDH (central carbon metabolism enzymes) to limit glucose use and lactate production, synergistically inhibiting cancer via MAPK and metabolic pathway suppression. Similarly, ursolic acid targets the MEK/ERK upstream cascade, suppressing ERK phosphorylation in NSCLC cells. This inhibition directly attenuates the activation of downstream transcription factor CREB, thereby blocking the transcriptional expression of gelatinases MMP-2 and MMP-9. The anti-invasive activity of ursolic acid is mediated by suppressing the MEK/ERK/CREB-mediated expression of MMP-2 and MMP-9, combined with the simultaneous induction of RECK, an endogenous MMP-9 inhibitor, which together potently inhibit ECM degradation (Son and Lee, 2020). Thus, the inhibition of the MEK/ERK pathway by these medicinal and edible substances presents a stark contrast to its aberrant activation by environmental carcinogens, highlighting the significant interventional value of medicinal and edible substances. For example, in head and neck squamous cell carcinoma, nicotine, a primary component of tobacco smoke, activates the CHRNA5 receptor, upregulates carboxylesterase 1 expression, and leads to sustained activation of the MEK/ERK signaling axis, thereby driving tumor cell migration and invasion, as demonstrated in (Feng C. et al., 2024). Given that smoking is the predominant risk factor for LC this CHRNA5-CES1-MEK/ERK oncogenic axis is likely to play a similarly central role in the initiation and progression of LC. Therefore, medicinal and edible substances capable of targeting this pathway, such as ursolic acid and lactucin, not only provide a molecular basis for countering the cancer-promoting effects of nicotine and other environmental carcinogens but also establish a mechanistic foundation for their potential role as chemopreventive agents in LC management. Other medicinal and edible substances regulating LC through cellular mechanisms include lobetyolin and lobetyol (Wang M. C. et al., 2022), Alpinia officinarum Hance extract (Alasmary et al., 2019), and the extract of Foeniculum vulgare Mill. (Ke et al., 2021).

Collectively, cellular regulation represents the most prevalent mechanism by which medicinal and edible substances affect LC, primarily through inducing tumor cell apoptosis and inhibiting tumor cell proliferation, invasion, and metastasis.