Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities


Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-derived metabolites play complex roles in supporting cancer progression and suppressing immune responses. Preclinical and clinical studies have shown that manipulating cholesterol metabolism inhibits tumour growth, reshapes the immunological landscape and reinvigorates anti-tumour immunity. Here, we review cholesterol metabolism in cancer cells, its role in cancer progression and the mechanisms through which cholesterol metabolites affect immune cells in the tumour microenvironment. We also discuss therapeutic strategies aimed at interfering with cholesterol metabolism, and how the combination of such approaches with existing anti-cancer therapies can have synergistic effects, thus offering new therapeutic opportunities.


Cholesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers1,2,3. Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened4,5, and by facilitating the formation of specialized membrane microdomains6,7.

Brief overview of cholesterol metabolism

Every mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras8. Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.

Fig. 1: Hallmarks and key drivers of cholesterol metabolism in the TME.

a, Cholesterol-biosynthesis pathway. Starting from acetyl-CoA, HMG-CoA is generated and further synthesizes mevalonate. This process is mediated by HMGCR, the first rate-limiting enzyme in cholesterol biosynthesis. Mevalonate is then converted to FPP, which has several uses: (1) production of GGPP for protein prenylation; (2) contribution to N-glycosylation; (3) production of ubiquinone and (4) providing squalene for cholesterol synthesis. Squalene is then converted to 2,3-epoxysqualene by SQLE and further to lanosterol by OSC. Cholesterol is used as a precursor to generate: (1) CE by ACAT1 or ACAT2, (2) oxysterols by enzymatic or non-enzymatic conversion, (3) vitamin D, (4) bile acids and (5) steroid hormones. b, In the TME, cholesterol metabolism is generally enhanced, thus supporting cancer progression, as evidenced by four aspects as shown: (1) enhanced cholesterol biosynthesis, (2) increased exogenous cholesterol uptake by LDLR, (3) elevated cholesterol esterification by ACAT1 and (4) increased oxysterol production. Intrinsic drivers include: (1) activation of oncogenes such as MYC, thus leading to mevalonate-pathway activation and further upregulating miR-33b expression, and consequently increasing MYC expression through positive feedback; (2) c-Fos-mediated suppression of transcription of LXRα (official symbol NR1H3), thus decreasing LXRα signalling and promoting cholesterol biosynthesis; (3) loss of p53-mediated repression of the mevalonate pathway, in a process relying on the target ABCA1; (4) SQLE-mediated inhibition of PTEN expression and activation of Akt, thus leading to CE accumulation. Extrinsic cues comprise ER stress, low pH and inflammatory regulators, thus directing mature SREBP2 (mSREBP2) translocation into the nucleus for activation.

Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis9. Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10,11,12). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs13. Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, including ABCA1, ABCG1, ABCG5 and ABCG8, or converted to less toxic cholesteryl esters (CEs) by acyl-coenzyme A:cholesterol acyltransferases (ACATs; also known as SOATs) and then stored in lipid droplets or secreted within lipoproteins14,15.

Cholesterol concentrations at both the cellular and systemic levels are subject to stringent and fine-tuned regulations. The master transcriptional regulators governing cholesterol homeostasis include sterol regulatory element–binding protein-2 (SREBP-2), liver X receptors (LXRs) and nuclear factor erythroid 2 related factor-1 (NRF1). Accumulation of cholesterol and cholesterol-derived oxysterols inactivates the SREBP-2 pathway by inducing insulin-induced gene (INSIG)-mediated retention of the SREBP-cleavage activating protein (SCAP)–SREBP-2 complex in the endoplasmic reticulum (ER), thereby downregulating cholesterol biosynthesis and uptake16. Meanwhile, desmosterol, the immediate precursor of cholesterol in the Bloch biosynthetic pathway, and oxysterols bind and activate LXRs, thereby enhancing the expression of genes involved in cholesterol efflux such as ATP-binding cassette subfamily A member 1 (ABCA1) and others such as myosin regulatory light chain interacting protein (MYLIP, also known as IDOL)17. High cholesterol concentrations also prevent nuclear translocation of NRF1 and block its inhibition of the LXR pathway18. Under conditions of cholesterol deficiency, the three regulatory pathways function in a coordinated and opposing manner, thereby ensuring an increase in cholesterol biosynthesis and uptake as well as a decline in cholesterol efflux and esterification.

Reprogrammed cholesterol metabolism in cancer cells

Hallmark features of cancer cholesterol metabolism

As fast-proliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth19. In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion20,21,22,23. As a consequence, cholesterol depletion or trafficking blockade hinders tumour growth and invasion in a variety of cancers24,25,26,27.

Increased cholesterol biosynthesis and uptake

Increased cholesterol biosynthesis is a hallmark of many cancers. In situations in which lipids and/or oxygen is limited, such as in the glioblastoma microenvironment, the master transcription factor SREBP2 and its downstream targets, including mevalonate-pathway enzymes, are significantly upregulated in tumors28. Beyond SREBP2, another transcription factor, RORγ, activates the cholesterol-biosynthesis program and facilitates progression of triple-negative breast cancer29.

Cholesterol biosynthesis also has a critical role in maintaining cancer stem cells by activating cellular signalling pathways downstream of sonic hedgehog, Notch and receptor tyrosine kinases30. Furthermore, elevated cholesterol biosynthesis is observed in patient-derived cancer stem cells under mammosphere culture conditions31. These lines of evidence suggest that ensuring a sufficient cholesterol supply for the cancer stem cell population may be essential to support cancer progression, thus highlighting a fundamental role of cholesterol in cancer cells.

In addition, the upstream mevalonate pathway is oncogenic in a variety of cancers32. Besides producing cholesterol, the mevalonate pathway has other fundamental consequences on cells (Fig. 1a). For example, the mevalonate pathway is required for protein prenylation, which directly regulates the function of Ras-family small GTPases33. This pathway also promotes the production of ubiquinone (also known as coenzyme Q10 or CoQ10), thereby supporting mitochondrial electron transport in p53-deficient cancer cells34. Moreover, ferroptosis suppressor protein 1 (FSP1) uses ubiquinone to limit excess lipid peroxidation, thus protecting cells from ferroptosis35,36. Hence, upregulation of the mevalonate pathway promotes tumourigenesis in various ways.

Compared with time- and energy- consuming de novo cholesterol synthesis, increasing cholesterol uptake might be more efficient for cancer cells. An extreme example is that of some anaplastic large cell lymphoma cells, which fully rely on cholesterol uptake to acquire cholesterol, owing to loss of SQLE, a rate-limiting enzyme in the cholesterol-biosynthesis pathway37. These cancer cells actively upregulate the LDLR, which takes up exogenous cholesterol as an alternative strategy to support proliferation. In addition, loss of SQLE leads to accumulation of the upstream precursor squalene, which protects cells against ferroptosis by maintaining the adequate composition of membrane polyunsaturated fatty acids.

Unexpectedly, lower levels of LDLR but higher levels of SQLE are expressed in advanced-stage prostate cancer, thus indicating a greater reliance on cholesterol synthesis than uptake38. In contrast to the LDLR, the high-density-lipoprotein receptor (also known as SR-BI) is upregulated in some prostate cancer samples39. In the case of intestinal tumourigenesis, both cholesterol synthesis and uptake contribute40. Although cholesterol uptake is an important source of cholesterol for cancer cells, how cells orchestrate cholesterol biosynthesis and uptake during cancer progression is complex and remains to be clarified.

Enriched cholesterol derivatives: cholesteryl esters and oxysterols

Accumulation of CE is another common signature in cancer. CE is usually stored in lipid droplets, ubiquitous cytosolic organelles that serve as a reservoir for neutral lipids such as CEs and triacylglycerols41. ACAT1 is the key enzyme that converts cholesterol to CE in most tissues and appears to exert a pro-tumour function, for example in pancreatic cancer and lymphocytic leukemia42,43. Inhibition of ACAT1 significantly impedes prostate cancer progression44. Treatment with the ACAT1 inhibitor CP-113818 significantly decreases breast cancer cell migration capability45. In glioma patient samples, ACAT1 knockdown dramatically impedes tumour progression in a nude-mouse xenograft model46. In patients with hepatocellular carcinoma, proteomic and phospho-proteomic analyses have indicated elevation of ACAT1 as a prominent feature. Application of the ACAT1 inhibitor avasimibe markedly represses tumour growth in an ACAT1-high-expression patient-derived-xenograft model47. In line with these findings, another CE-metabolic enzyme, lysosomal acid lipase, is upregulated and subsequently promotes cell proliferation in clear cell renal cell carcinoma, thus suggesting active CE metabolism in these cells48.

Therefore, CE appears to serve as a reservoir of cholesterol that cancer cells can tap under increased demand. This function also explains the cancer-associated upregulation of the relevant enzymes such as ACAT1 and lipase, which ensures rapid conversion between esterified and free cholesterol. Importantly, this CE-as-reservoir strategy provides substantial benefits when cancer cells are challenged with unfavourable stimulation such as drug treatment, as discussed in the last section of this Review.

Beyond CEs, oxysterols are another group of cholesterol metabolites enriched in the tumour microenvironment (TME)49. With cholesterol as a precursor, oxysterols can be generated by enzymatic or non-enzymatic oxidative processes. Although this oxidation leads to chirality of oxysterols, which might affect their functions, only several oxysterols have been precisely defined with R/S nomenclature to date. For example, 24S-hydroxycholesterol is abundant in the brain, and 22R-hydroxycholesterol is the first metabolite in the steroid-hormone-biosynthesis pathway50. Functional oxysterols, including 25-hydroxycholesterol (25HC), 27-hydroxycholesterol (27HC), 24-hydroxycholesterol (24HC), 22-hydroxycholesterol (22HC), 7α/β-hydroxycholesterol and 7-ketocholesterol, exert broad functions by binding nuclear receptors such as LXR and ROR49,51.

Extensive studies have been performed to elucidate the effects of 27HC on cancer cells. In patients with oestrogen-receptor-positive breast cancer, 27HC is elevated in both breast tissues and tumours52. Treatment to elevate 27HC promotes cell proliferation and tumour growth by modulating a series of genes including oestrogen-receptor signalling genes such as ARMT1 and PARD6B as well as genes involved in the GDFN–RET signalling pathway. A similar function of 27HC facilitates breast cancer metastasis to the lung53. Additional functions of 27HC in breast cancer progression include: (1) a decrease in p53 activation by enhancing p53 E3 ligase MDM2 function and promoting cell proliferation54, (2) activation of STAT3–VEGF signalling, thus facilitating angiogenesis55, and (3) induction of epithelial–mesenchymal transition and matrix metallopeptidase 9 expression, thus promoting cell migration and invasion56.

Because oxysterols are known LXR ligands that repress SREBP signalling, they are likely to inhibit cell proliferation. Indeed, 27HC together with 24(R/S), 25-epoxycholesterol dampens gastric cancer cell proliferation and migration via modulation of LXR signaling57. Similarly, 27HC treatment impedes cell proliferation in colorectal cancer cells, but this effect is mediated by decreased activating phosphorylation of the kinase Akt rather than LXR activation58. In addition to 27HC, other oxysterols such as 7-ketocholesterol, cholestane-3β-5α-6β-triol and 5α-cholestane-3β,6β-diol can impede cell-cycle progression and trigger apoptosis in multiple human and mouse cancer cell lines59. Collectively, oxysterols can be both friend and foe for cancer cells, depending on the particular tumour context. Oxysterols also have multiple functions in shaping the immunological landscape, as discussed in the next section.

Because active cholesterol metabolism has an essential role in promoting cancer progression, understanding the key factors driving altered cholesterol pathways in cancer cells is critical, as summarized in Fig. 1b.

Intrinsic drivers of cholesterol metabolism

Gain of oncogenes and loss of tumour suppressors are key characteristics of cancer cells. Interestingly, these features correspond well with fluctuations in cholesterol metabolism. In normal retinal pigment epithelium cells, activation of Akt leads to upregulation of SREBP and its target genes in the cholesterol pathway60, thus suggesting a positive correlation between oncogene activation and cholesterol metabolism. The oncogene MYC is required for upregulation of the mevalonate pathway in patient-derived brain-tumour-initiating cells61. This upregulation of the mevalonate pathway further upregulates the microRNA miR-33b, thus increasing MYC expression and establishing a positive feedback loop facilitating tumour growth. In hepatocytes, transgenic expression of the oncogene c-Fos represses LXRα signalling and elevates the production of cholesterol and cholesterol-derived metabolites such as oxysterols and bile acids62, which in turn is associated with increased inflammation and hepatocellular carcinogenesis. Whereas oncogene activity promotes cholesterol upregulation, tumour suppressors have the opposite effect. For example, the well-known tumour suppressor p53 upregulates the cholesterol-efflux transporter ABCA1, thereby restricting SREBP2 maturation and subsequently repressing the mevalonate pathway63. Furthermore, suppression of the mevalonate pathway by statins appears to effectively retard tumourigenesis in p53 loss-of-function cancer.

Beyond de novo cholesterol biosynthesis, tumour-suppressor activity restricts cholesterol uptake and esterification. In prostate cancer, loss of the tumour suppressor phosphatase and tensin homolog (PTEN) activates PI3K–Akt signalling and leads to accumulation of CE by increasing cholesterol uptake and causing further esterification44. Consistently, in hepatocellular carcinoma induced by non-alcoholic fatty liver disease, SQLE expression is dramatically elevated. Enhanced levels of SQLE cause downregulation of PTEN expression and subsequent activation of Akt signalling, thus increasing CE levels and facilitating cancer development64. In summary, whereas oncogenes promote active cholesterol biosynthesis and facilitate tumour growth, tumour suppressors antagonize this overactivated state and maintain cholesterol homeostasis (Fig. 1b). Therefore, loss of tumour suppressors during tumourigenesis leads to dysregulation of cellular cholesterol metabolism.

Extrinsic cues affecting cholesterol metabolism

Acidification of the TME

Secretion of protons and CO2 from cells as a result of glycolysis is well known to contribute to acidification of the TME65. These low-pH conditions increase cholesterol biosynthesis. In pancreatic cancer, when the extracellular pH decreases to 6.8, SREBP2 translocates to the nucleus and activates expression of downstream target genes66. Importantly, 12 low-pH-responsive genes are associated with the SREBP2 pathway and are inversely correlated with patient survival66.

The inflammatory TME

Inflammation is closely associated with cancer development through multiple mechanisms67. In hepatocellular carcinoma cells, treatment with the pro-inflammatory factor lipopolysaccharide activates both cholesterol biosynthesis and uptake68. This effect is mediated by two components of the NF-κB signalling pathway, IKKα and TAB3, which are negatively regulated by miR-195. Interestingly, enhanced cholesterol levels further strengthen NF-κB signalling in a positive feedback loop. Furthermore, long-term (24-hour) stimulation by the cytokine TNF promotes SREBP2 activation and facilitates macrophage polarization69. Although this process occurs in macrophages, TNF in the TME is likely to also influence cholesterol metabolism in cancer cells.

TME-induced ER stress

An accumulation of unfolded or misfolded proteins in the ER triggers the unfolded-protein response, in which release of the ER chaperone Grp78 leads to activation of ER signalling proteins such as PERK, IRE1 and ATF6. This induction of the unfolded-protein response results in either removal of misfolded proteins or cell death, depending on the degree of accumulation of misfolded proteins70. In the harsh conditions of the TME, hypoxia and low nutrient concentrations induce ER stress and the unfolded-protein response in an adaptive response71. The ER is the primary location of cholesterol biosynthesis, esterification and oxidation, and ER cholesterol levels have a predominant role in determining SREBP2 activation. Therefore, ER stress might be expected to affect cholesterol metabolism. Accordingly, docosahexaenoic acid treatment induces ER stress in the colorectal cancer cell line SW620 and is accompanied by upregulation of key genes in cholesterol metabolism, such as HMGCR, SREBF2 and NPC1 (ref. 72). Although the effect of docosahexaenoic acid on SREBP2 activation is independent of ER stress, ER stress markedly increases SREBP2 levels73. However, understanding of how ER stress regulates cholesterol synthesis is preliminary, and further investigation is warranted.

In summary, cancer cells respond to unfavourable extrinsic environments by activating cholesterol biosynthesis, thus allowing for cellular adaptation and better survival (Fig. 1b).

Functions of cholesterol and cholesterol-derived metabolites in the TME

In addition to containing cancer cells, tumours contain a variety of immune-effector cells and immunosuppressive cells—collectively referred to as tumour-infiltrating immune cells (TIIs), which have diverse anti-tumour or pro-tumour functions, depending on cancer type and stage74. TIIs include T lymphocytes, B lymphocytes, tumour-associated macrophages (TAMs), dendritic cells (DCs), myeloid derived suppressor cells (MDSCs), neutrophils and natural killer cells75. In this section, we summarize the diverse effects of cancer-derived cholesterol metabolites, especially oxysterols, on TII functions (Fig. 2).

Fig. 2: Immune-modulation functions of cancer-derived oxysterols.

Various oxysterols are secreted in the TME and regulate immune cell functions. For neutrophils, 22HC binds CXCR2 and recruits Gr-1-high neutrophils to cancer cells; 24HC attracts Ly6G- and CD11b-positive neutrophils; 27HC increases neutrophils and γδT cells but decreases CD8 T cells, thus promoting breast cancer metastasis. For macrophages, 25HC attracts macrophages by directing cytoskeletal reorganization, thus probably contributing to cancer metastasis, and also promotes cancer metastasis by upregulating the expression of matrix metallopeptidases (MMPs). For DCs, potential oxysterols that activate LXRα inhibit CCR7 expression, thereby suppressing DC function. An unknown tumour-derived factor (TDF) leads to accumulation of oxidized neutral lipids such as CE and decreases MHC-I peptide expression on the cell surface, thus dampening DC antigen-presentation ability. For CD8 T cells, some oxysterols presumably activate LXR signalling and suppress the effector function. For MDSCs, yet-undefined factors recruit LOX-1-positive MDSCs, which exert pro-tumour functions.

Enrichment in immunosuppressive cells

Neutrophils are emerging as an important immunosuppressive population in the TME76,77, thus prompting the question as to which molecular factors guide neutrophils into the TME. Specifically accumulating in the conditioned medium of various cancer cells, 22HC can recruit CD11bhighGr1high neutrophils78. Unexpectedly, in this context, 22HC binds and activates the G-protein-coupled receptor C-X-C motif chemokine receptor 2 (CXCR2) instead of LXR to recruit neutrophils. In addition, 24HC and 27HC can recruit neutrophils in other cancer types. In pancreatic neuroendocrine tumours, elevation of 24S-hydroxycholesterol by hypoxia-inducible factor-1a (HIF1α) attracts neutrophils, thus promoting angiogenesis79. Moreover, in a breast cancer model based on high-cholesterol-diet feeding, 27HC has been found to attract polymorphonuclear neutrophils and γδ T cells but to deplete cytotoxic CD8 T cells, thereby promoting tumour metastasis80.

MDSCs share high similarity with neutrophils but also display unique features77. A recent discovery has characterized lectin-type oxidized LDL receptor-1 (LOX-1) as a prominent marker distinguishing polymorphonuclear myeloid-derived suppressor cells from neutrophils81. LOX-1 overexpression has been confirmed in different human cancers and correlated with poorer survival rates. Because LOX-1 is an LDL receptor, these observations hint at reprogramming of cholesterol metabolism in MDSCs in the TME, thus prompting the question of how LOX-1 overexpression influences MDSC function in establishing an immunosuppressive microenvironment.

Beyond neutrophils and MDSCs, TAMs can also be reprogrammed as a result of alterations in cholesterol metabolism. Cancer cells secrete hyaluronic acid oligomers, thereby increasing cholesterol efflux in TAMs and directing TAMs towards an M2-like phenotype that accelerates tumour progression82. Moreover, 25HC interacts with G-protein-coupled receptor 183 and triggers migration of both macrophages and human blood monocytes by reorganizing the cytoskeletal protein vimentin83. In addition to these effects on TAMs, 25HC can advance gastric cancer cell metastasis by promoting matrix metallopeptidase expression, without affecting cell proliferation and apoptosis84. Together, these lines of evidence indicate that oxysterols affect immunosuppressive cells and consequently facilitate cancer development.

Inhibiting immune-effector cells

Similarly to cancer cells, activated T cells also undergo rapid proliferation and therefore depend on elevated cholesterol metabolism to supply enough cholesterol to be used as building blocks. Whereas SREBP2 signalling has been shown to be essential for CD8 T cell proliferation and effector function85, LXR signalling negatively regulates T cell activation86. Therefore, oxysterols enriched in the TME might inhibit T cell anti-tumour immunity via LXR activation, whereas upregulation of intrinsic cholesterol biosynthesis or uptake in T cells could augment T cell anti-tumour function.

Inhibition of the cholesterol-esterification enzyme ACAT1 reprograms cholesterol metabolism in CD8 T cells, thus leading to accumulation of free cholesterol at the plasma membrane87. Cholesterol then directly binds T cell receptors and facilitates nanoclustering, which promotes antigen-induced signalling and the consequent upregulation of cholesterol biosynthesis and uptake88. Moreover, cholesterol aids in establishing a mature immunological synapse for targeted killing of cancer cells.

In contrast, cholesterol accumulation in the TME has been shown to trigger ER stress and further increase T cell exhaustion in a study using several well-known surface markers, such as PD-1, TIM-3 and LAG-3, to examine T cell exhaustion89. However, these markers can also reflect T cell activation. Furthermore, the cause of T cell ER stress could be cholesterol metabolites such as oxysterols rather than cholesterol itself. In an in vitro polarized CD8 T cell subset, Tc9, much lower levels of cholesterol are needed to produce the signature cytokine IL-9 than in the Tc1 CD8 T cell subset, thus reflecting the heterogeneity of cholesterol metabolism in different T cell subsets90. Therefore, it will be important to carefully compare cholesterol metabolism in different tumour-infiltrating T cell subsets, such as effector versus memory, functional versus dysfunctional, and helper versus killer. In addition, the functions of extrinsic and intrinsic cholesterol might differ. Upregulation of intrinsic cholesterol biosynthesis and uptake might be beneficial, whereas too much or too little extrinsic cholesterol might cause T cell dysfunction.

Inhibition of antigen presentation

Conditioned medium from several cancer cells can activate LXR-α signalling in DCs, thus decreasing expression of CC chemokine receptor-7 (CCR7) on the DC surface91. In agreement with a role of CCR7 in mediating lymphoid homing of DCs, CCR7 inhibition dampens DC migration from tumour beds to draining lymph nodes and consequently suppresses the presentation of tumour antigens to T cells. Blockade of cholesterol synthesis in tumour-bearing mice or inactivation of LXR-α ligand by expression of SULT2B1b, a cholesterol sulfotransferase that converts oxysterol to inactive sulfated oxysterol, restores DC functionality as well as the anti-tumour response91. However, the exact oxysterol that exerts these effects remains to be identified. Additionally, tumour-derived factors have been shown to directly cause accumulation of oxidized neutral lipids including CE, triacylglycerols and fatty acids in DCs, thus decreasing levels of peptide–MHC class I complexes on the cell surface and the presentation of exogenous antigens92.

Targeting cholesterol metabolism for cancer therapy

Targeting cholesterol synthesis

Because of the vital and varied functions of cholesterol metabolism in cancer progression, impeding active cholesterol metabolism, for example via inhibition of the mevalonate pathway, has been demonstrated to be a feasible anti-tumour strategy93,94 (Table 1). To date, statins, HMGCR inhibitors, have been the most widely used cholesterol-metabolism-targeting drugs in clinical studies for patients with cancer. In general, statins are safe at standard doses, showing only mild adverse effects on the muscle and liver95. Side effects vary depending on the exact statin used, as well as the dosage and combination with other drugs. Nevertheless, even for patients with cardiovascular disease and abnormal liver function, statins remain safe to use and improve the results of liver tests (concentrations of serum alanine aminotransferase or aspartate aminotransferase)96.

Table 1 Anti-cancer therapies that target cholesterol metabolism

For patients with cancer, numerous clinical studies have suggested benefits of statin usage on patient survival. Patients receiving statins for at least 5 years have been found to have a 47% lower risk of colorectal cancer than non-statin users, after adjustment for other known risk factors97. In another study, statins decreased patient mortality across various cancer types, regardless of whether they were taken before or after cancer diagnosis98,99,100,101. Experiments on leiomyoma have shown that simvastatin treatment not only inhibits cell proliferation and enhances cell apoptosis, but also suppresses levels of extracellular matrix proteins102.

Unexpectedly, statins and other mevalonate-pathway inhibitors have been found to act as vaccine adjuvants103. Lipophilic statin can effectively decrease geranylgeranylation of the small GTPase Rab5, which is involved in endosomal trafficking, thus eventually enabling better antigen presentation and tumour-suppressive responses. A synergistic effect has been observed when statins are combined with anti-PD1 therapy. Notably, although statins are well-known cholesterol-pathway inhibitors, they might target other pathways as well. For instance, statin treatment in various cancer cells leads to a striking elevation of mitochondrial membrane potential without affecting cholesterol levels104.

Other enzymes in the cholesterol-biosynthesis pathway can also be targeted pharmacologically (Table 1). SQLE, which catalyses squalene oxidization, is considered to be an oncogene and has been evaluated as an anti-tumour target105. Several drugs against SQLE have been clinically approved as antifungals, and whether they can be repurposed as anti-tumour drugs should be investigated. Ro 48-8071, an inhibitor of oxidosqualene cyclase (OSC), an enzyme that converts 2,3-oxidosqualene to lanosterol, significantly suppresses growth and metastasis of both colorectal cancer and pancreatic cancer106. Application of this inhibitor decreases cell proliferation, increases cell apoptosis and impairs cancer cell migration. More importantly, Ro 48-8071 synergizes with 5-fluorouracil, thus eliciting an enhanced anti-tumour effect; these results suggest that potential benefits might arise from combination therapy. Zaragozic acids, which inhibit squalene production, effectively repress both lymphoma and Lewis lung carcinoma growth without causing clear toxic side effects107. These inhibitors could potentially be used together with anti-cancer vaccination or adoptive immunotherapy for increased anti-tumour efficacy.

Cancer cells should not be assumed to always require high cholesterol levels, nor should any anti-tumour strategy be assumed to necessarily limit cholesterol biosynthesis: exceptions can exist. For instance, inhibition of Ephrin type-A receptor 2 impairs ABCA1 function and decreases cholesterol efflux, thus resulting in membrane rigidity and cell apoptosis in triple-negative breast cancer cells108. Similarly, in a mouse model of hepatocellular carcinoma, a cholesterol-rich diet raises membrane cholesterol levels, and consequently increases CD44 relocation into membrane lipid rafts and decreases the interaction between CD44 and the actin-binding protein Ezrin, thus restricting metastasis109. Collectively, whereas inhibiting cholesterol biosynthesis is a plausible and promising therapeutic strategy to treat cancer, modulating cholesterol levels at the plasma membrane might provide a novel alternative approach.

Targeting cholesterol esterification

In the previous section, we outlined the positive roles of CE in cancer progression. Developing inhibitors against CE is of high clinical interest (Table 1). In an imatinib-resistant chronic myelogenous leukaemia cell line, inhibition of CE by the ACAT1 inhibitor avasimibe suppresses tumour growth and subsequently restores imatinib sensitivity by downregulating MAPK signaling110. In prostate cancer, avasimibe treatment impairs the Wnt–β-catenin pathway and thus suppresses metastasis111. Application of avasimin, a nanomedicine version of avasimibe encapsulated with human serum albumin112, specifically induces cancer cell apoptosis and is effective in tumour xenograft models.

Bitter-melon extract has also been reported to downregulate CE accumulation by inhibiting ACAT1 expression in triple-negative breast cancer cells113. Bitter-melon-extract treatment also effectively decreases mammosphere xenograft growth.

In addition to having direct effects on cancer cells, CE inhibition affects human chimeric antigen receptor–modified T cells. Administration of avasimibe augments the in vitro cytotoxic effect of these cells, an effect that can be partly explained by an increased ratio of cytotoxic CD8 T cells114. This observation is consistent with findings showing that avasimibe treatment effectively promotes CD8 effector T cell function87,115. Thus, targeting CE has dual benefits, by repressing cancer cells on the one hand and augmenting CD8 T cell anti-tumour function on the other hand.

Targeting LXR signalling

LXR agonists have shown promising results for the treatment of a variety of cancers, mainly by inhibiting cancer cell proliferation and inducing apoptosis116,117,118. However, modulating LXR signalling affects not only cancer cells but also immune cells (Table 1). The LXR agonist RGX-104, which efficiently represses growth of a broad range of mouse and human tumors119, depletes MDSCs through upregulation of the LXR transcriptional target APOE and subsequently increases T cell activation. Importantly, this observation has been further validated in patients with cancer in a phase I clinical trial. Moreover, LXR activation can augment other immunotherapies such as adoptive T cell transfer and checkpoint-blockade therapy in mouse models119.

Beyond efforts to exploit LXR activation to suppress cancer cell growth and boost anti-tumour immune responses, the effects of LXR repression on cancer progression have been tested. The LXR inverse agonist SR9243 recruits an LXR corepressor that represses LXR activity, thus inducing massive apoptosis in cancer cells120. In this context, LXR inhibition effectively impairs tumour growth by suppressing lipogenesis and glycolysis. Furthermore, the effects of both the LXR agonist LXR623 and the inverse agonist SR9243 on clear cell renal cell carcinoma have been examined121. Both drugs effectively decrease cancer cell proliferation and induce apoptosis. Whereas SR9243 predominantly suppresses lipogenesis by inhibiting enzymes such as acetyl-CoA carboxylase, fatty acid synthase and stearoyl-CoA desaturase 1, LXR623 significantly decreases cellular cholesterol content by promoting cholesterol efflux and limiting cholesterol uptake. Together, this evidence suggests that both excessive LXR activity and insufficient LXR activity are unfavourable for cancer cells.

Combination strategies

Accumulating evidence indicates that targeting cholesterol metabolism sensitizes cancer cells to other anti-tumour therapies (Table 1). Here, we summarize two different benefits of combination therapy.

First, in some cancer cells, a combination strategy limits cell-surface-receptor-mediated oncogenic activation more effectively than single therapies. For instance, in breast cancer cells positive for Erb-b2 receptor tyrosine kinase (ErbB2, also known as HER2), suppression of cholesterol biosynthesis by inhibitors such as lovastatin can trigger ErbB2 internalization and degradation122. In this scenario, use of ErbB2 inhibitors such as lapatinib and neratinib together with lovastatin dramatically represses tumour growth. In prostate cancer cells, administration of the anti-androgen drug enzalutamide upregulates enzymes such as HMGCR in the mevalonate pathway. HMGCR inhibition by simvastatin further suppresses androgen signalling by lowering androgen-receptor levels via repression of signalling by mammalian target of rapamycin. A combination therapy of enzalutamide and simvastatin has been shown to have a significant synergistic effect on tumour suppression123.

Second, in other cancer cells, cholesterol-metabolism-blockade therapy causes feedback responses that decrease drug efficacy. Therefore, inhibiting feedback responses with another therapy might enhance anti-tumour efficacy. For example, although fluvastatin treatment can repress colony formation in breast cancer cells, HMGCR expression is induced as a compensatory mechanism. Because AMP-activated protein kinase (AMPK) activation by agonists, such as aspirin or metformin, blocks this feedback on HMGCR, a combination treatment combining aspirin or metaformin with fluvastatin has been found to almost completely abrogate the colonization capability of breast cancer cells124. In another recent study, statin treatment has been found to significantly decrease levels of the mevalonate-pathway product coenzyme Q in cancer cells, thus leading to excessive oxidative stress125. Given that cancer cells can upregulate antioxidant pathways by enhancing cystine import and consequently decrease oxidative stress, the use of AZD6244—an inhibitor of mitogen-activated protein kinase kinase (MEK), which limits cystine import—in combination with statins has been shown to be highly cytotoxic in cancer cells125.

Other than inhibiting cholesterol biosynthesis, inhibition of cholesterol esterification is also an option in combination strategies. One possible strategy is a combination of cholesterol-esterification inhibitors with traditional chemotherapy drugs. For example, the combination of avasimibe with well-known chemotherapy drugs such as gemcitabine126, paclitaxel127 or doxorubicin128 increases anti-tumour effects in tumour models. Another strategy is combining cholesterol-esterification inhibitors with immunotherapies, such as anti-cancer vaccines and anti-PD-1 therapy. Although avasimibe treatment effectively inhibits regulatory T cell populations and increases CD8 T cell infiltration in a lung tumour model, a combination of avasimibe with a Kras peptide vaccine has stronger tumour inhibitory effects115. Avasimibe can also be combined with a DC vaccine to boost adaptive anti-tumour immunity, as shown in a head and neck cancer model129. Finally, a combination of avasimibe with anti-PD-1 therapy effectively controls melanoma growth87.


Numerous lines of evidence support the concept that cholesterol metabolism is critical for cancer progression. Intrinsic and extrinsic cues are now understood to drive reprogramming of cholesterol metabolism in the TME, and cancer-derived cholesterol metabolites are understood to exert immunomodulatory functions. Therapeutic targeting of cholesterol metabolism in both cancer cells and immune cells is likely to move towards clinical application.

Despite exciting progress in the field, many fundamental questions remain to be addressed, such as: How does cholesterol metabolism preferentially help cancer cells but harm immune cells? Do other cholesterol metabolites contribute to cancer progression and immunosuppression apart from the well-studied oxysterols? Can a specific cholesterol pathway be modulated to achieve both anti-tumour and pro-immune effects? What are the most effective combination strategies that attack cancer cells with different approaches? Could some drugs that are currently used for the treatment of metabolic diseases be repurposed as anti-tumour drugs? These outstanding questions reflect the urgent need for more mechanistic studies of cholesterol metabolism in cancer, which might pave the way for next-generation therapies.


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We thank T. Horng at ShanghaiTech University for language editing, and X. He and L. Mu for figure design. C.X. is funded by CAS grants (Strategic Priority Research Program XDB29000000, Facility based Open Research Program QYZDB-SSW-SMC048, Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation), NSFC grants (31861133009, 31621003), a MOST grant (2018YFA0800700) and the Ten Thousand Talent Program “Leading talent” of China.

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C. X. designed the framework. B.-L.S. wrote the first section, and B.H. wrote the rest of the manuscript. C.X. revised the manuscript.

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Correspondence to Chenqi Xu.

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C.X. is a scientific co-founder of Hangzhou MetMed Therapeutics. The other authors declare no competing interests.

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Peer review information Primary Handling Editor: Christoph Schmitt.

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Huang, B., Song, B. & Xu, C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab 2, 132–141 (2020).

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