Sterol regulatory element binding proteins (SREBPs), liver X receptors (LXRs) and nuclear factor erythroid 2 related factor-1 (NRF1) are the main transcription regulators regulating cholesterol homeostasis (7).

SREBPs can affect cholesterol synthesis by regulating the activity of HMGCR. Some studies have found that the inhibition of HMGCR is significantly related to the reduction of incidence rate of epithelial ovarian cancer (8). However, this finding does not indicate that drugs that inhibit HMGCR can reduce their risk of disease, and further research is needed to understand whether similar associations exist with these drugs. In addition, it was found that SREBP1c and SREBP-2 were not overactivated in mouse tumors after injection of diethylnitrosamine to induce hepatocellular carcinoma (9). Therefore, further in-depth research is needed on the role of SREBPs in tumor cells. Another key enzyme for cholesterol synthesis, squalene epoxidase (SQLE), is also regulated by SREBPs. The SQLE transcription gene can inhibit PTEN protein expression, activate Akt signaling, and lead to cholesterol ester accumulation ( Figure 1 ). A study by the Chinese University of Hong Kong confirmed that SQLE can promote the proliferation of colorectal cancer (CRC) cells by inducing cell cycle progression and inhibiting apoptosis, and confirmed that the SQLE inhibitor terbinafine can inhibit the growth of CRC through synergistic effects with oxaliplatin and 5-fluorouracil (10).

LXRs are nuclear receptors encoded by the gene nr1h3 (LXR-α) and nr1h2 (LXR-β), some functional oxysterols, such as 24-hydroxycholesterol (HC), 25-HC and 27-HC, are important activators of LXRs. In breast cancer, LXR-α Cancer cell lines with high mRNA expression are more sensitive to the inhibition of 22 (R)-HC induced (11), and estrogen receptor status is negatively correlated with the ability of LXR to induce typical target gene expression, that is, LXR in breast cancer cells with negative estrogen receptor has a stronger ability to induce typical target gene expression (12).

NRF1 can also affect cholesterol homeostasis by influencing the above two regulatory factors. When cholesterol concentration increases, it blocks the nuclear translocation of NRF1 and inhibits its inhibition of the LXR pathway. NRF1 can also regulate the activation of SREBPs and lipid metabolism by regulating of endoplasmic reticulum transmembrane protein 33 (10).

In the tumor microenvironment, the endogenous and exogenous signals of cells can reprogram cholesterol metabolism, thus promoting the occurrence of tumors (13). The following mainly introduces the carcinogenic signal pathways related to abnormal cholesterol metabolism.

The activation of PI3K/AKT/mTOR signal can upregulate intracellular cholesterol levels (14), which is an important pathway for regulating cell cycle and is directly related to cell dormancy, proliferation, carcinogenesis, and lifespan. Methoxyvalerate can activate PI3K, mTOR, NF-κB, and inhibit the transcription of genes such as P21 and P27 (15), leading to changes in apoptosis, cycle, autophagy, and migration of cancer cells (13). Hanai et al. (16) reported that ATP citrate lyase (ACL) exerts anti-tumor effects by downregulating the PI3K/AKT pathway. Studies have also revealed a CRC liver metastasis specific cholesterol metabolism pathway: hepatocyte growth factors from the liver environment activate the c-Met/PI3K/AKT/mTOR axis in CRC cells to activate the SREBP2 dependent cholesterol biosynthesis pathway (17).

Lysosomal cholesterol can inhibit mTORC1 signal through the SLC38A9 Niemann Pick C1 (NPC1) complex (13). Studies have shown that the deletion of the NPC1 gene leads to cholesterol accumulation in lysosomes, leading to excessive activation of mTORC1, impaired mitochondrial function, and neurodegeneration (18). In addition, Niemann Pick C1 like 1 gene knockout has been shown to prevent the occurrence of colitis related cancer (14). MTORC1 may become a new target for inhibiting tumor progression (18).

Mevalonate can further activate Hippo signal by activating the TP53/SREBP pathway in cancer cells (15). P53 is a key tumor suppressor factor that maintains metabolic homeostasis and coordinates cellular stress responses. The p53 and Hippo pathways collaborate at multiple levels to fine-tune SREBP activity and regulate cholesterol/lipid levels (19). The TP53 gene change is often observed in poorly differentiated thyroid cancer and undifferentiated thyroid cancer, which may lead to the disruption of cell cycle checkpoints and DNA repair mechanisms, leading to the tolerance of tumor cells to cumulative genetic instability (20). It was found that TP53 mediated activation of cholesterol synthesis via SREBP pathway can induce breast cancer cell proliferation and self-renewal through preacylation of GTPases (14).

The Hedgehog pathway is a classic cancer-related signal pathway controlled by G-protein coupled receptors, known as Smoothened receptors. It has been reported that cholesterol could activate cancerigenic Hedgehog signaling by binding to Smoothened receptors at first hand (21). Cholesterol can also covalently modify proteins, including smoothened and hedgehog, and promote the formation of specialized membrane microdomains to regulate the signal pathway of tumorgenesis and cancer progression (7).

Furthermore, cholesterol specifically binds to the PDZ domain of scaffold proteins, for example, the N-terminal PDZ domain of NHERF1/EBP50. NHERF1/EBP50 is a master regulator of oncogenic signal networks that is involved in cell proliferation and tumor formation by assembling cancer-associated proteins, including those belonging to the PI3K/Akt and Wnt/β-catenin pathways (15).

RTK/Ras signal is a major regulatory gene that induces the synthesis of cholesterol and leads to intracellular cholesterol accumulation by activating the SREBP transcription factor, mutations and activation of which are common in childhood acute myeloid leukemia (14).

In summary, cholesterol is mainly regulated by transcription factors such as SREBPs, LXRs, NRF1, and there are also connections between these regulatory factors. Importantly, cholesterol metabolism can affect multiple carcinogenic pathways, including PI3K/AKT/mTOR, NF-κB,WNT/β-catenin, Hedgehog, TP53/SREBP, NPC1/mTOR, RTK/Ras, and other signal pathways related to regulating tumor cell proliferation, growth, and angiogenesis. Some transcription factors related to tumors are also affected by cholesterol metabolism. In summary, cholesterol metabolism, including cholesterol regulatory factors, is closely related to tumor carcinogenic signal pathways and promotes tumor progression, potentially becoming a key target for tumor treatment.

It is worth noting that lipid metabolism is also regulated by epigenetic imprinting. It includes DNA methylation, post translation histone modification and non-coding RNA.

Hypercholesterolemia can promote tumor growth, especially with an increase in low-density lipoprotein (LDL) (36). Epidemiological studies have shown that LDL and ox-LDL are closely related to breast cancer, colorectal cancer, pancreatic cancer and other malignant tumors, suggesting that LDL and ox-LDL play an important role in the occurrence and development of cancer (37). Recently, it has been found that LDLR is overexpressed in various cancers, such as hepatocellular carcinoma, breast cancer, colorectal cancer, prostate cancer, etc. Due to the fact that cancer cells require more cholesterol to obtain energy than normal cells, they may increase cholesterol levels through receptor-mediated endocytosis of LDL (38). Abnormal lipid metabolism can lead to lipid toxicity, leading to oxidative stress and significantly increasing levels of reactive oxygen species (ROS). The gradual increase in oxidative stress can lead to the oxidation of intracellular LDL to ox-LDL. Ox-LDL binds to lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) and Cluster Differentiating 36 (CD36), inducing mutations, leading to inflammation, cell proliferation, and cancer metastasis. In addition, oxidative stress promotes DNA damage in cancer, leading to malignant transformation and carcinogenesis (39). Elevated plasma ox-LDL was detected in breast cancer, gastric cancer and colon cancer (36). Yang L et al. also demonstrated that oxidized low-density lipoprotein induced by hypercholesterolemia can promote the generation of bladder cancer stem cells through the CD36/STAT3 signal axis (40). Due to the complex roles of LDL and ox-LDL in cancer, further research is needed to investigate the potential therapeutic effects of lipid metabolism in cancer treatment.

Some observational study have found that the reduction of high-density lipoprotein cholesterol (HDL-C) level is also related to some cancer types, such as CRC, lung cancer, breast cancer, ovarian cancer, thyroid cancer and gastric cancer (41). However, whether the decrease in HDL-C levels is a consequence or causal factor in the development and progression of cancer remains a controversial issue. Breast cancer patients have low levels of HDL-C, so some people think that low levels of HDL-C may be a risk factor for breast cancer (42). In addition, low HDL-C levels are associated with a high risk of gastric cancer, high lymphatic and vascular infiltration rates, advanced lymph node metastasis, and poor prognosis (33). Ganjali S et al. also proposed that low levels of HDL-C are significantly associated with cancer mortality (39). There are also studies analyzing that malignant cells consuming higher cholesterol to promote tumor growth may lead to plasma cholesterol depletion (43), which may be the reason for the above research results. However, some studies have found that SR-B1-mediated HDL uptake can enhance cell proliferation in breast cancer, prostate cancer and ovarian cancer, but these effects may be cancelled by the antioxidant and anti-inflammatory properties of HDL (4). Some scholars also believe that cancer type may be an important factor affecting the relationship between HDL-C and cancer (41), but the specific mechanism may require further research.

Obviously, the relationship between cholesterol and cancer may not be a simple dual factor relationship, and there may be a potential conditional factor that can reverse the relationship between cholesterol and cancer progression. One possible conditional factor is the tissue origin of cancer, where different tissues have different cholesterol requirements and composition ratios. Another possible conditional factor is the daily intake of cholesterol, and different dietary habits may affect the epigenetic regulatory factors of cancer development. And these ideas require more statistical analysis and experimental research to further elucidate.

Sphingolipid has been proved to be a key signal molecule in many pathophysiological processes such as inflammation, cancer, metabolic diseases, neurodegenerative diseases, and lysosomal storage diseases (52). Ceramide and sphingosin-1-phosphate (S1P), two central bioactive lipids of sphingolipid, play opposing roles in regulating cancer cell death and survival respectively (53).

Ceramide is synthesized through three pathways, namely, de novo synthesis pathway, sphingomyelin hydrolysis pathway and salvage pathway. The de novo synthesis route is to generate ceramide from palmitic acid and serine through a series of steps such as condensation, reduction and dehydrogenation. It is then transported to Golgi apparatus through vesicles or ceramide transporters, and then further converted into other sphingolipids, such as sphingomyelin and complex glycosphingolipids. Sphingomyelin hydrolysis pathway is that sphingomyelinase decomposes sphingomyelin in cell membrane to produce ceramide. The remedy is to utilize the circulation of sphingosine, reuse the long chain sphingosine, and reform ceramide under the catalysis of ceramide synthase (CERS). The rescue pathway also involves the circulation of exogenous short chain C2~6 ceramide to generate endogenous long chain C14~26 ceramide, which exerts a variety of signal functions in cancer cells, such as inhibiting proto oncogene protein Myc and telomerase (54).

Ceramide, as the central molecule of sphingolipids metabolism, is the precursor of all sphingolipids synthesis. Ceramide can be converted into ceramide-1-phosphate (C1P) and sphingomyelin by ceramide kinase (CERK) and sphingomyelin synthase, respectively. Ceramide can also produce sphingosine under the hydrolysis of ceramidases, and sphingosine can participate in the ceramide recovery pathway or be phosphorylated by SPHK1/SPHK2 (sphingosine kinase) to produce sphingosine 1-phosphate (S1P).

In the ceramide metabolic pathway, glucose ceramide synthase (which can decompose ceramide) is associated with the drug resistance of head and neck cancer or liver cancer cells to chemotherapy drugs. The high expression of CERS6 is closely related to the poor prognosis of ovarian cancer. Shi Y et al. have confirmed that the knockout of CERS6 inhibits the proliferation, invasion, metastasis and apoptosis of serous ovarian cancer cells, and regulates cell cycle by affecting AKT/mTOR/4EBP1 signal pathway (54). In addition, p53 regulates specific ceramide biosynthesis through direct transcriptional activation of CERS6 and induces cell death in p53 wild-type human lung cancer cells (55). The study of Chen H et al. for the first time proved that CERS6 can be used as a treatment sensitive biomarker for the chemotherapy response of triple negative breast cancer patients (56). In addition to CERS6, CERS2 (57), CERS1 (58), and CERS4 (59) have also been proven to be associated with tumor progression. Similarly, CERK/C1P pathway plays a prominent role in regulating the growth, survival and spread of cancer cells (60). Activation of CERK/C1P pathway inhibits the formation, metastasis and migration of A549 lung cancer cells (61). Rivera IG et al. also demonstrated that CERK expression/activation and C1P may be related factors regulating migration and invasion of human pancreatic cancer cells (62). The inhibition of CERK restricts AKT activation and translocation to mitochondria in mutant KRAS lung cancer, blocks phosphorylation of mitochondrial membrane potential related protein VDAC, thus affecting iron ptosis and cancer cell survival (63). In triple negative breast cancer, the up regulation of CERK is significantly related to its chemoresistance, which may be mediated by the up regulation of Ras/ERK and PI3K/Akt pathways (64). It is worth noting that CERK has become a common therapeutic target for triple positive and triple negative breast cancer cells (65). The inhibition of acid ceramidase in CDase family causes mitochondrial dysfunction and oxidative stress in pancreatic cancer cells, thus playing an anti-tumor role (66). Upregulation of acid ceramidase was also observed in prostate cancer (67). Ceramide transfer proteins also play an indispensable role in tumor progression. Ceramide transfer protein inhibits ceramide metabolism by enhancing/inhibiting epidermal growth factor receptor and lysosomal associated membrane glycoprotein 2, thereby inducing cancer cell death or reducing drug resistance (53). S1P is also a potential target for tumor therapy. Studies have shown that increased levels of S1P were detected in the SPHK2 knockout mice, which exacerbates chronic intestinal inflammation, and through S1PR1–NF-κB-IL-6 (interleukin-6)–STAT3 (activator of transcription factor 3) signal leads to the development of colitis related cancers (54). Analysis of metabonomics and network pharmacology shows that the effective anti-cancer component of Weijing Tang - tricin inhibits tumor growth primarily by inhibiting PRKCA/SPHK/S1P signal and anti-apoptotic signal (68). All these evidences indicate that sphingomyelin and ceramide occupy an important position in tumor progression.

The length of ceramide acyl chain determines its function. Long-chain species (C16-C20) increase cell death, oxidative stress and insulin resistance, cell death and oxidative stress, while derivatives of very long chain (C>22) have the contrary effect. In the model mice injected with diethylnitrosamine for hepatocellular carcinoma, most ceramide species were induced, and the ratio of long-chain and very long-chain ceramide increased (9). Haberl EM et al. confirmed that ceramide mediates the anticancer effect of different chemotherapy drugs, and restoring ceramide level can inhibit human hepatocellular carcinoma, and speculated that short chain ceramide can prevent tumor progression. However, ceramide increased in mouse tumors and decreased in human hepatocellular carcinoma tissues (69). Therefore, the model of hepatocellular carcinoma induced by diethylnitrosamine is not suitable for testing new drugs targeting neoadipogenesis or ceramide metabolism, but can be used to study how tumors escape the cytotoxicity of ceramide (9).

The glycosphingolipids are divided into neutral and acid glycosphingolipids (including gangliosides, glucuronic acid glycoproteins with glucuronic acid, sulfated glycan phospholipids, and phosphate glycosphingolipids) according to their electric charges. Next, gangliosides are mainly introduced.

Gangliosides are glycosphingolipids on the surface of cells, which widely exist in mammalian cell membranes. There are many types of gangliosides, among them, disialogangliosides GD2 and GD3 and O-acetylated derivatives are considered to be markers of the origin of tumor neuroectoderm. Fucosyl monosialogliosides (GM1) are also overexpressed in many cancers, especially in small cell lung cancer (70). The synthetic pathways of these tumor related gangliosides are briefly described as follows: first, the first sialic acid residues catalyzed by the GM3 synthetase ST3Gal V are transferred in Golgi bodies by lactoceramide (LacCer, Gg2Cer) to form GM3 (the precursor of a series gangliosides); then the sequential action of β4GalNAc T1 and β3Gal T4 is used to extend GM3 and form GM1; and then GM1 was α-1,2-Fucosyltransferase (FUT1 and FUT2) were further fucosylated; Alternatively, the function of GD3 synthase ST8SIA1 converts GM3 into GD3 (precursor of b series gangliosides); Finally, GD3 and GD2 can be acetylated by CASD1 sialic acid O-acetyltransferase at C9 position of sialic acid to form 9-O-acetylated GD3 (9-OAcGD3) and 9-O-acetyl GD2 (9-OAcGD2), respectively, β 4GalNAc T1 and β The impact of 3GalT4 on OAcGD3 and OAcGD2 is unclear.

Gangliosides and the enzymes responsible for ganglioside metabolism are associated with many types of cancer. For example, increased expression of GD3 synthase and/or GD2 synthase mRNA is frequently observed in cancer; the promoter region of ST8SIA1 gene has been found to be relatively overexpressed in glioblastoma, melanoma and breast cancer cell lines; GD2-positive tumors highly express OAcGD2, such as sarcoma, neuroblastoma, glioma, breast cancer and small cell lung cancer cells; A large proportion of small cell lung cancer expressed very high levels of Fuc-GM1; High levels of OAcGD3 are shown in melanoma (70). Dr. Yu Wengong and his team found that ST3GaIV promotes lung metastasis of breast cancer in mice, which proves that O-GIcNAc glycosylation of protein significantly promotes tumor occurrence and metastasis, and reveals its mechanism of action. Other relevant factors need further explanation. In addition, gangliosides also regulate various growth factor receptors (GFR), including tyrosine kinase GFR, platelet derived GFR, fibroblast GFR and epidermal GFR mediated cell growth and proliferation (52).

In the process of cholesterol and triglyceride metabolism, cholesterol itself, as the end point and starting point of lipid metabolism, is related to the progress, invasion and drug resistance of breast cancer, non-small cell lung cancer (97) and other cancers (98). Metabolic enzymes can also affect tumor resistance by increasing metabolic intermediates. Fatty acid synthase is a key enzyme in the fat formation pathway, and its overexpression leads to cancer resistance to genotoxicity drugs by increasing DNA repair. The HMGCR inhibitor simvastatin can also enhance the efficacy of capecitabine chemotherapy by inhibiting NF-kB regulated markers of proliferation, invasion, angiogenesis, and metastasis (99). In addition, the expression of metastasis associated genes 1, acetyl CoA synthase 2 (100), stearyl CoA desaturase, and 12 lipoxygenase (101) in human colon cancer can enhance chemotherapy resistance to platinum drugs or paclitaxel by regulating lipid metabolism (99, 102). Some transporters, such as ABC transporters, have been identified to be associated with multiple drug resistance, resulting in resistance of cancer cells to 5-FU, vincristine, cisplatin and other chemotherapy drugs (103). In addition, cholesterol regulatory factors such as SREBP2 can be induced and activated by Caspase-3 (cysteine enzyme 3) to promote cholesterol biosynthesis, thus leading to resistance to targeted antiangiogenic drugs, including sorafenib or lovatinib, by driving the activation of Hedgehog signal pathway (104). In addition to platinum and plant-based chemotherapy drugs, antibiotic drugs such as penicillin can make cells re sensitive to oxaliplatin by inhibiting FAO and promoting intracellular ROS accumulation (105). Other chemotherapy drugs, such as doxorubicin, lower the rate limiting enzyme HMGCR levels of cholesterol synthesis (106). On the contrary, cyclophosphamide has no effect on blood lipids. These data indicate that the different effects of chemotherapy drugs on lipid metabolism may also be related to drug efficacy. Multiple types of chemotherapy drugs and targeted anti angiogenic drugs inevitably exhibit resistance, and targeted lipid metabolism may become a new approach to address resistance at present.

During sphingolipid metabolism, SPHK1 is a lipid kinase that phosphorylates sphingosine to generate S1P. S1P has been proved to be positively correlated with chemotherapy resistance of breast cancer, colorectal cancer and non-small cell lung cancer (107). The study of Qin Z et al. showed that SPHK1 was positively related to the cisplatin resistance of bladder cancer cells, and showed anti apoptotic effect by down-regulation of apoptosis related protein and up-regulation of anti-apoptotic protein (Bcl-2) in overexpression cell lines (107). Its potential mechanism of inducing cisplatin resistance and apoptosis inhibition may be to activate STAT3 by binding to the octamer containing non POU (with highly conserved DNA binding domain) domain, and become a potential new target for bladder cancer treatment. Many evidences show that activated SphK1 is involved in tumor genesis and resistance. Ceramide and sphingosine metabolic enzyme inhibitors and synthetic ceramide can be used as sensitizers for radiotherapy and chemotherapy of head and neck squamous cell carcinoma (108). Phosphatidylcholine has been identified as significantly associated with tumor resistance. Phosphatidylcholine is hydrolyzed by phospholipase A2 to produce lysophosphatidylcholine and arachidonic acid (AA), and COX-2 catalyzes the conversion of AA to prostaglandin E2. Liao et al. reported that when cytosolic phospholipase A2α is targeted, the Ras/MEK/ERK and Akt/b catenin signal pathways are inhibited, ultimately enhancing the effectiveness of chemotherapy (109). Hemolytic phosphatidylcholine acyltransferase 1 converts lysophosphatidylcholine into phosphatidylcholine in the presence of acyl coenzyme a. In gastric cancer, the expression of lysophosphatidyl acyltransferase 1 is significantly up-regulated, which promotes the proliferation of cancer cells, improves the survival period, and enhances the ability of cell migration of cancer (110). Chen et al. demonstrated that artificial inhibition of phospholipase A2 can increase the chemical sensitivity of gastric cancer cells to 5-Fu (111).

The regulation and epigenetics of adipocytes, lipid droplets, and ester rafts also play an important role in tumor resistance. Studies have shown that pancreatic cancer cells can induce adipocytes to dedifferentiate into CAA. CAA promotes the malignant characteristics of cancer through the expression of SAA1, suggesting that SAA1 is a new therapeutic target for cancer. Moreover, extracellular vesicles derived from adipocytes can reduce the susceptibility to ferroptosis in CRC and mediate resistance to oxaliplatin. In addition, the accumulation of LDs drives the death resistance of CRC cells to 5-fluorouracil and oxaliplatin treatment (112). Keratin 6 can enhance resistance to cisplatin by regulating the formation of lipid rafts (113). Interestingly, epigenetics is also associated with tumor chemotherapy resistance, for example hypermethylation of miR-129-5p induces resistance of gastric cancer cells to chemotherapy drugs such as 5-FU, vincristine, and cisplatin (100).

It is worth noting that lipid metabolism also affects chemotherapy resistance by changing the immune microenvironment. Mesenchymal stromal cells (MSCs) in the tumor microenvironment are considered as important factors to promote the development of chemotherapy resistance. As an important component of the tumor environment, MSCs can promote chemotherapy resistance and help cancer cells overcome the anticancer effects of chemotherapy drugs by secreting protective cytokines, even product gene mutations and alter transcriptional expression. In gastric cancer, MSCs can promote self-renewal and chemotherapy resistance of tumor cells through fatty acid oxidation (FAO). And the FAO inhibitor Etomoxiry can significantly reverse stem cell characteristics and resistance to 5-FU and oxaliplatin (114). Interestingly, an existing study shows that co culture of MSCs with gastric cancer cells activates FAO in gastric cancer cells, thereby enhancing chemotherapy resistance (115). In addition, MSCs can also up regulate non-coding RNA AGAP2-AS1 to affect the expression of CPT1 (carnitine palmitoyltransferase 1), thereby promoting FAO and chemotherapy resistance of breast cancer (116). These results indicate that tumor cells can interact with mesenchymal stem cells to promote tumor cell metabolic reprogramming and drug resistance.

Immunotherapy is currently an important method for tumor treatment. At present, the most widely used immunotherapy drugs are blocking antibodies targeting immunosuppressive receptors, such as PD-1 (Programmed Cell Death Protein-1), PD-L1 (Programmed Death Ligand-1), CTLA-4 (Cytotoxic T Lymphocyte Associated Protein 4), etc. (117). In recent years, compared to CTLA-4, anti PD-1 antibodies have shown stronger clinical efficacy and superior tolerance. However, powerful as anti-PD-1 antibody also inevitably develop resistance. The mechanism of anti PD-1 antibody resistance is still unclear, which may be related to TYRO3 (118), KRAS (119) and other gene mutations, and the mutation rate of the tumor itself (117), β-catenin related immune escape (120), the expression level of PD-1 in the tumor itself (117) and IFN-γ related to the disruption of tumor signal pathways. Due to the presence of drug resistance, the response rate of many tumors to immune checkpoint inhibitors is only between 20% -40% (121). So, it is very important to address the resistance of immune checkpoint inhibitors. At the same time, targeted lipid metabolism demonstrates the ability to enhance the efficacy of immunotherapy. In tumor immunotherapy, LXR activation therapy produces a strong anti-tumor response in mice and enhances T cell activation in various immunotherapy studies, suggesting that the lipid metabolism regulatory factor LXR may be a target for improving the efficacy of tumor immunotherapy (15). In addition, the expression of key lipogenic enzymes such as acetyl CoA carboxylase is significantly negatively correlated with the infiltration level of CD8+T cells and immune cell lysis activity in gastric cancer, indicating that inhibiting acetyl CoA carboxylase can enhance the anti-tumor immunity of gastric cancer (122). Although there is currently no clinical study on the combination of immune checkpoint inhibitors and targeted lipid metabolism drugs, targeted lipid metabolism is likely to bring more significant clinical efficacy to immunotherapy. Further exploration is needed on the relationship between lipid metabolism and immunotherapy resistance.

The above indicates that the metabolism of cholesterol, phospholipids, triglycerides, lipid rafts, lipid droplet formation, and epigenetics play an indispensable role in the development of tumor resistance. Lipid metabolism is closely related to tumor chemotherapy and immunotherapy resistance, including lipid regulatory factors, lipid metabolism related enzymes, and lipid metabolism intermediates. Some studies have shown that regulating lipid metabolism can enhance the effectiveness of chemotherapy and immunotherapy, so targeted lipid metabolism combined with chemotherapy is expected to become a critical method to address tumor resistance.

Statins are a cholesterol lowering drug that selectively inhibits HMGCR, and their anti-tumor properties are receiving increasing attention. Statins inhibit the development of cancer cells by blocking the valproate pathway and damaging the YAP/TAZ (the main transcription regulator of normal organ growth and tumor growth) dependent transcriptional response (14). Statins including pivastatin (123), fluvastatin (15) and simvastatin (124) have been proved to be effective in inhibiting tumor cell proliferation and angiogenesis and promoting cell apoptosis. Its possible mechanisms include: inhibiting Akt and Braf/MEK/ERK1/2 pathways to prevent cell growth and promote cell apoptosis (15); Pre acylated Ras/Raf/MEK and PI3K/Akt/mTOR signal pathways inhibit tumor endothelial cell growth (123); Increase the expression of miR-140-5p, thereby inhibiting proliferation and inducing apoptosis (12). It is worth noting that Hu T et al. found that pivastatin is also effective in the chemotherapy resistance of lung cancer cells (123). A clinical trial for breast cancer patients showed that they received high-dose atorvastatin (80mg/day) 2 weeks before surgery. This treatment reduced the proliferation of breast cancer by affecting the expression of cyclin D1 and p27 (125). In addition, statins can also manipulate lipid rafts to affect tumor development by lowering cholesterol levels. The consumption of cholesterol in the lipid raft of non-small cell lung cancer can inhibit the phosphorylation of lipid raft related non receptor tyrosine kinase Src and the dislocation of local adhesion complex of lipid raft (14), which is related to tumor formation, cell migration and invasion. Statins can also induce autophagy, iron death, and affect the tumor microenvironment to play an anti-tumor role, but the specific mechanism is still questionable (125).

Compared with hydrophilic statins (such as pravastatin and rosuvastatin), lipophilic statins (such as simvastatin) show greater ability to penetrate cell membranes and passively diffuse into hepatocytes and non-hepatocytes, as well as higher apoptosis promoting activity (126). Due to its high cytotoxic potential, lipophilic statins may be beneficial for cancer treatment. Lipophilic statins act as EMT signaling pathway antagonists in breast cancer stem like cells by inhibiting the mevalonate pathway (125).

In summary, statins can affect tumor progression through various factors, such as tumor cell proliferation, angiogenesis and apoptosis, as well as chemotherapy resistance. However, in clinical studies, statins have not shown any inhibitory effect on tumors. We collected clinical studies on statins and tumor progression from Pubmed, including all randomized controlled trial studies ( Table 1 ), and collected some information to better understand the current research status of statins in tumors.

Yamasaki et al. demonstrated that beta drugs can reduce the proliferation of cancer cells and promote cell apoptosis (127). Some studies have shown that fenofibrate can induce p53 protein accumulation and reprogram the tumor’s immune microenvironment in HPV positive head and neck squamous cell carcinoma (128). Chen L et al. showed that fenofibrate showed antitumor activity in vitro and in vivo through mitochondrial and metabolic Reprogramming (129). In addition, fenofibrate also inhibits mTOR-p70S6K signal and induces cell death in human prostate cancer cells (130). However, a systematic review and meta-analysis of 17 long-term randomized placebo-controlled trials in 2012 showed that the impact of beta drugs on cancer was neutral (131). Therefore, higher quality research or larger scale experimental studies are needed to demonstrate the correlation between beta drugs and tumors.

The precursor invertase Bacillus subtilisin/Coxin 9 (PCSK9) could regulate cholesterol metabolism by connecting LDLR, and reduce cholesterol circulation by targeting lysosomes to destroy receptors (132). Inhibition of PCSK9 by gene deletion or PCSK9 antibody can increase the expression of major histocompatibility protein class I protein on the surface of tumor cells, and promote the strong tumor invasion of cytotoxic T cells (133). However, the relationship between PCSK9 and tumor needs further proof.

A study on pancreatic and glioma cancer cells showed that methyl-β-Cyclodextrin depletes cholesterol in cell membranes and destroy lipid rafts, leading to an increase in CD44 extracellular lipid distribution, and promoting CD44 related tumor metastasis mediated by ADAM-10, a metalloproteinase (72). methyl-β-Cyclodextrin can also inhibit cell growth and cell cycle arrest through the expression of cyclin A and D1 mediated by prostaglandin E (2) independent pathway (134), and inhibit endothelial adhesion of monocytes induced by lipopolysaccharide or oxidized low-density lipoprotein (135). The above indicates methyl β-Cyclodextrin may become a new drug for tumor therapy.

As a cholesterol absorption inhibitor, studies have also found that ezetimibe can demonstrate its anti-tumor effect by inhibiting angiogenesis (15).

Acid sphingomyelinase (SMase) causes sphingomyelin to hydrolyze into ceramide, thereby inducing apoptosis of p53 defective glioblastoma cells (136). Overexpression of acidic SMase makes glioma cells sensitive to chemotherapy, gemcitabine and doxorubicin (137). The activation of neutral SMase in C6 glioma cells is believed to increase the activation of mitogen activated protein kinase through the up regulation of ceramide, thus leading to apoptosis (136). Sphingomyelinase inhibitors may contribute to tumor therapy. In addition, the development of small molecule drugs that inhibit the activity of acid ceramidase is a promising method to improve the standard cancer treatment and clinical results of patients (67).

In addition, nanoparticle mediated CERK siRNA delivery and hydrogel mediated continuous delivery of CERK inhibitors to tumor sites can also inhibit tumor progression (65).

It is worth noting that the mRNA in the exosomes can be transferred to the receptor cells and play a role in the receptor cells (92). Therefore, exosomes can be designed to deliver different therapeutic payloads, including short interfering RNA, antisense oligonucleotide, chemotherapy drugs and immunomodulators, and have the ability to deliver them to the desired target. The lipid and protein composition of exosomes can affect their pharmacokinetic properties, and their natural components may play a role in improving bioavailability and reducing adverse reactions (96).

Epigenetic related demethylation and histone modification drugs are also new anticancer therapies. Wang B et al. believe that the dexcitabine based regimen can serve as an alternative first-line chemotherapy regimen for elderly patients with acute myeloid leukemia (138). And it shows anti-tumor activity in prostate cancer and non-small cell lung cancer. The possible mechanism is that the silencing of tumor suppressor genes induced by DNA methylation is relieved.

In addition, viruses are also used to combat tumor cells. Oncolytic virus is a kind of virus that can specifically infect tumor cells and induce their death. But at present, only one oncolytic virus - genetically modified herpesvirus T-VEC has been approved by the US FDA for the treatment of melanoma.

From radiochemotherapy drugs to targeted therapy to immunotherapy, as well as a variety of tumor treatment methods including interference RNA and oncolytic virus, human beings have made an unprecedented attempt to defeat tumors. Although drug resistance has always been a problem, targeted lipid metabolism is still expected to become a promising anti-tumor strategy.