Tumor cells actively increase lipid uptake from the TME to meet their high metabolic demands. Lipid transporters such as CD36 and aquaporin 7 (AQP7) are upregulated, enhancing the import of fatty acids and glycerol, respectively (13). CD36 facilitates the uptake of long-chain fatty acids, which are then used to fuel energy production and biosynthetic pathways (14). This process has been linked to enhanced metastatic potential in multiple cancers, including breast and ovarian cancers (15, 16). And AQP7 favors the glycerol uptake of cancer cell, which can be used in triglyceride synthesis, contributing to lipid storage and energy production (17).

In normal mammalian cells or tumor cells, fatty acids can be stored in lipid droplets or undergo lipolysis for immediate energy use. The enzyme hormone-sensitive lipase, encoded by LIPE gene, is involved in lipolysis, breaking down stored triglycerides into free fatty acids that can be used for energy production (18). This process is crucial for tumor cells to generate ATP during periods of metabolic stress (19). Lipid droplets serve as an energy reservoir, and their accumulation has been associated with increased survival under nutrient-poor conditions. For instance, in hepatocellular carcinoma (HCC), lipid droplets provide a ready supply of fatty acids for energy production when needed, giving tumor cells a survival advantage in fluctuating environments (20).

FAO is a key metabolic pathway that cancer cells utilize to generate ATP, particularly under nutrient-limited conditions (21). By oxidizing fatty acids, tumor cells can sustain their energy needs even when glucose is scarce. The enzyme carnitine palmitoyltransferase 1 (CPT1) is crucial for transporting fatty acids into the mitochondria for oxidation, and its upregulation has been associated with increased aggressiveness and resistance to therapy in several cancers, including prostate cancer and melanoma (22, 23). For example, recent evidence suggests that lymph node metastasis require a metabolic shift towards FAO mediated by MITF, a transcription factor, in MYC⁺ melanoma. Additionally, inhibiting FAO in MYC⁺ melanoma cells could effectively reduce lymph node metastasis favored by MITF, which provided a potential therapeutic approach in melanoma dissemination (24).

Tumor cells also employ lipid-detoxifying enzymes to manage the buildup of toxic lipid byproducts. Aldo-keto reductase family 1 member C1 (AKR1C1) is one such enzyme that helps detoxify reactive lipid species, protecting tumor cells from lipid-induced oxidative damage (25). This detoxification mechanism is vital for maintaining cellular integrity and supporting tumor survival, particularly in the lipid-rich environment of many tumors.

Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, has emerged as a crucial metabolic vulnerability in melanoma (26). While ferroptosis can limit tumor growth, melanoma cells frequently upregulate antioxidant defense mechanisms, such as glutathione peroxidase 4 (GPX4), to escape ferroptotic cell death. GPX4 neutralizes lipid peroxides, protecting melanoma cells from oxidative damage and promoting their survival within the lipid-rich tumor microenvironment. Recent studies indicate that inducing ferroptosis in melanoma cells enhances T cell-mediated cytotoxicity and overcomes PD-1 blockade resistance. For example, inhibition of GPX4 or acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme that promotes lipid peroxidation, significantly enhances the efficacy of ICIs in melanoma models (27). Additionally, tumor-infiltrating Tregs have been shown to secrete, further dampening immune responses (28). Targeting ferroptosis regulators may therefore serve as a novel therapeutic approach to sensitize melanoma cells to immunotherapy.

Cancer cells often exhibit increased de novo lipid synthesis to support rapid proliferation. FASN is a key enzyme in this pathway, producing fatty acids that are essential for membrane formation, energy storage, and signaling. Elevated FASN expression is common in several cancers, including breast and prostate cancers, and is associated with poor prognosis (29, 30). The overactivity of FASN not only facilitates tumor growth but also contributes to immune evasion by altering membrane composition and signaling pathways, ultimately creating a more favorable environment for tumor survival. For instance, recent studies have shown that small-molecule MHC-II inducers can promote immune detection and anti-cancer immunity by modulating cancer metabolism, including lipid processing pathways (31). These inducers help boost the immune system’s ability to recognize and attack tumor cells by enhancing antigen presentation, thereby shifting the metabolic balance away from tumor survival and towards immune-mediated clearance.

Cholesterol is another important lipid that plays a role in cancer progression. Tumor cells often increase cholesterol synthesis and uptake to support membrane fluidity and the formation of lipid rafts, which are involved in cell signaling (32). Elevated cholesterol levels in the TME can also contribute to immune suppression. In colorectal cancer, increased cholesterol levels have been linked to the exhaustion of T cells, reducing their effectiveness in targeting tumor cells (33). By promoting T cell dysfunction, altered cholesterol metabolism aids tumor cells in evading the immune response.

Lipids also act as signaling molecules that influence the behavior of both tumor cells and stromal cells within the TME. Bioactive lipids such as prostaglandins, sphingolipids, and lysophosphatidic acid (LPA) play critical roles in promoting inflammation, angiogenesis, and immune modulation (34). A recent study found, in pancreatic cancer, lipid-derived signals contribute to the recruitment of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), which help the tumor evade immune detection and foster a pro-tumorigenic environment (35).

Melanoma cells exhibit significant alterations in several lipid metabolic pathways, including FASN, β-oxidation, and cholesterol synthesis ( Table 1 ). One of the most well-studied features of melanoma metabolism is the increased activity of FASN, which catalyzes de novo fatty acid synthesis (36). FASN is responsible for the conversion of acetyl-CoA and malonyl-CoA into long-chain fatty acids, which are essential for membrane formation, energy storage, and signaling molecule production (37). Overexpression of FASN has been strongly associated with poor prognosis in melanoma patients, as elevated lipid synthesis fuels tumor cell proliferation, survival, and immune evasion (38). For example, inhibiting FASN has been shown to reduce melanoma cell viability, sensitize tumors to ICIs, and slow tumor progression (39). Given the significant role of FASN in melanoma, it represents a promising target for combination therapies aimed at improving immunotherapy efficacy.

In addition to fatty acid synthesis, β-oxidation plays a critical role in melanoma cell survival, particularly under nutrient deprivation (40). The process of β-oxidation breaks down fatty acids into acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle to produce ATP (41). Melanoma cells utilize this pathway to meet their high energy demands, especially in low-glucose environments typical of the TME. This metabolic flexibility allows melanoma cells to thrive in conditions that would normally be inhospitable. A recent research indicates that inhibiting FAO may impair the tumor’s ability to maintain its energy production, leading to reduced tumor survival under stress conditions (42). These findings suggest that FAO inhibitors could be an effective strategy to disrupt melanoma’s metabolic adaptability and improve outcomes in combination with ICIs.

Cholesterol metabolism is another key pathway dysregulated in melanoma. Cholesterol is integral not only to cell membrane structure but also to signaling pathways such as the PI3K/AKT and mTOR pathways, both of which are frequently activated in melanoma (43). Cholesterol has also been shown to play a role in immune suppression within the tumor microenvironment by promoting CD8⁺ T cell exhaustion, further facilitating immune evasion (8). Moreover, cholesterol metabolites, particularly 27-hydroxycholesterol, have been implicated in counteracting the effects of vemurafenib by promoting the growth of melanoma stem-like cells, thereby contributing to treatment resistance (44). Targeting cholesterol metabolism offers a promising avenue for therapeutic intervention. Inhibiting cholesterol synthesis has been shown to restore T cell function and enhance the efficacy of ICIs in preclinical melanoma models (45). These evidences position cholesterol metabolism as a critical target for overcoming immune resistance in melanoma patients.

The TME in melanoma is a complex and heterogeneous niche, where metabolic crosstalk between tumor cells and immune cells is pivotal in determining the tumor’s fate (46). Melanoma cells actively reprogram their lipid metabolism, sculpting the TME in ways that not only suppress anti-tumor immune responses but also facilitate tumor progression. This metabolic adaptation is critical for melanoma’s survival and growth, especially in the face of therapeutic challenges.

Hypoxia, a common feature of the TME, significantly influences lipid metabolism in melanoma (47). Under low oxygen conditions, hypoxia-inducible factors (HIFs) are activated, leading to the upregulation of FASN and redirecting glycolytic intermediates toward lipid biosynthesis (48). This adaptation enables melanoma cells to maintain membrane integrity and signaling capacity, ensuring their survival despite oxygen scarcity (49). Furthermore, hypoxia-induced lipid accumulation is associated with increased levels of signaling lipids, such as prostaglandins and sphingolipids, which are known to promote tumor progression and resistance to therapy (50). And these metabolites are known to contribute to an immunosuppressive microenvironment by dampening T cell activity and promoting the recruitment of immunosuppressive cells like MDSCs (51). The presence of MDSCs is linked to poorer prognosis in melanoma, emphasizing the critical interplay between lipid metabolism and immune evasion (52). Recent research has also shown that melanoma cells grown in hypoxic conditions were found to be more resistant to chemotherapy, which was linked to an increased reliance on lipid synthesis and storage (53). This evidence highlights the critical role that lipid metabolism plays in enabling melanoma cells to thrive in oxygen-poor environments, reinforcing their ability to evade cell death and resist therapeutic interventions.

In addition to hypoxia, melanoma cells are frequently subjected to nutrient deprivation, particularly a lack of glucose and essential amino acids, due to insufficient vascularization and increased metabolic demand (54). To survive under these conditions, melanoma cells reprogram their metabolism and increasingly rely on FAO as an alternative energy source (55). FAO plays a crucial role in maintaining ATP production when glucose is scarce, allowing melanoma cells to adapt to metabolic stress. For example, a study by Li, Xiao-Xue et al. demonstrated that melanoma cells exposed to low-glucose conditions exhibited a significant increase in FAO activity, which supported their continued growth and survival (56). This shift towards FAO enables melanoma cells to break down fatty acids into acetyl-CoA, which is then fed into the tricarboxylic acid (TCA) cycle to generate ATP. Importantly, this metabolic adaptation not only helps tumor cells endure periods of metabolic stress but also contributes to their aggressiveness by fueling continuous proliferation. Moreover, the reliance on FAO has been linked to resistance to therapy. Studies have shown that inhibiting FAO in melanoma cells sensitizes them to treatments, such as chemotherapy and targeted therapies, by depriving them of a critical energy source (57, 58). In particular, targeting key enzymes involved in FAO, such as CPT1, has been shown to impair tumor growth and enhance the effectiveness of cancer treatments in preclinical models (59). Hence, FAO plays a pivotal role not only in sustaining melanoma under nutrient-limited conditions but also in promoting resistance to standard therapies.

Recent advances in melanoma research have underscored the critical role of lipid metabolism in the dysfunction of CD8⁺ T cells within the TME. One of the key mechanisms involves the upregulation of CD36, a fatty acid transporter, which facilitates the increased uptake of fatty acids by tumor-infiltrating CD8⁺ T cells (60). This lipid overload induces oxidative stress and lipid peroxidation, leading to ferroptosis—a form of regulated cell death driven by lipid peroxides. As a result, CD8⁺ T cells experience diminished cytotoxic cytokine production and impaired antitumor capabilities, severely weakening their ability to eliminate melanoma cells (60). Importantly, studies have demonstrated that CD36 expression correlates with the upregulation of immune inhibitory receptors, such as PD-1 and TIM-3, further promoting T cell exhaustion and dysfunction (61). The metabolic stress induced by CD36-driven lipid accumulation not only triggers ferroptosis but also exacerbates T cell exhaustion, a state characterized by reduced proliferative capacity and effector function (62). This dysfunction is particularly pronounced in lipid-rich tumor environments, where the high availability of fatty acids perpetuates this deleterious cycle, effectively allowing melanoma cells to evade immune surveillance (63). Targeting these lipid metabolic pathways presents a promising therapeutic strategy. Inhibiting CD36 or blocking ferroptosis has shown significant potential in restoring CD8⁺ T cell function. Preclinical studies have demonstrated that these interventions can reinvigorate exhausted T cells and, more critically, enhance the efficacy of ICIs in melanoma (63, 64). By mitigating the lipid-induced metabolic dysfunction, such strategies offer a dual benefit: reversing immune suppression while simultaneously boosting the antitumor response.

Lipid metabolism plays a pivotal role in shaping the immunosuppressive function of both Tregs and MDSCs within the TME, thereby facilitating immune evasion and tumor progression.

Tregs rely heavily on lipid metabolism for their immunosuppressive function, particularly in the nutrient-deprived and immunosuppressive environment of tumors (65). FAO is essential for maintaining mitochondrial integrity and energy production in Tregs, which sustains their suppressive capacity (66). Recent studies show that the inhibition of fatty acid-binding proteins (FABPs), such as FABP5, disrupts mitochondrial integrity in Tregs, leading to the release of mitochondrial DNA and the activation of type I interferon (IFN) signaling pathways (67). This ultimately enhances IL-10 production, which bolsters the suppressive function of Tregs in the TME (67). Furthermore, lipid peroxidation poses a significant challenge to Treg function (68). Tregs are particularly susceptible to ferroptosis, a form of lipid-induced cell death. Glutathione peroxidase 4 (Gpx4) plays a key role in protecting Tregs from lipid peroxidation by neutralizing lipid hydroperoxides (69). Loss of Gpx4 in Tregs leads to impaired immune homeostasis and heightened ferroptosis, which, paradoxically, can enhance antitumor immunity by reducing Treg-mediated immune suppression (69).

MDSCs, another critical player in tumor-associated immune suppression, also depend on lipid metabolism to sustain their immunosuppressive activities. Tumor-derived factors, such as cytokines and prostaglandins, drive the differentiation and expansion of MDSCs within the TME. These myeloid cells are enriched in lipid metabolic pathways, including FAO and cholesterol synthesis, which enable them to thrive in the nutrient-poor environment of tumors and suppress the function of effector T cells (70). Moreover, increased prostaglandin E2 (PGE2) production, a common feature of lipid metabolism in tumors, has been shown to promote MDSC recruitment and enhance their suppressive function by inhibiting T cell responses and promoting the secretion of immunosuppressive cytokines such as IL-10 and TGF-β (71). Targeting lipid metabolic pathways, such as sphingosine kinase-1 (SK1) and PGE2, has been proposed as a strategy to reduce MDSC-mediated immune suppression and improve responses to immune checkpoint inhibitors (71).

Tumor-associated macrophages (TAMs) play a pivotal role in the metabolic reprogramming of the melanoma microenvironment. Recent single-cell transcriptomic analyses have identified subpopulations of lipid-associated TAMs (LA-TAMs) and angiogenic TAMs (Angio-TAMs) that exhibit distinct functions in melanoma progression. Notably, LA-TAMs1, which are enriched in lipid metabolism-related pathways, are more abundant in non-metastatic melanoma (NMM), whereas Angio-TAMs predominate in metastatic melanoma (MM) (72). These findings suggest that lipid metabolic adaptations within TAMs may shift macrophage polarization toward a more immunosuppressive and pro-metastatic phenotype, facilitating immune evasion and tumor progression. Targeting lipid metabolic pathways in TAMs could be an effective strategy to reprogram the tumor microenvironment and enhance the efficacy of immunotherapies.

Cholesterol metabolism plays a crucial role in cancer progression and immune evasion within the TME. Tumor cells exhibit altered cholesterol homeostasis to support their rapid proliferation and immune escape mechanisms (73). Elevated cholesterol biosynthesis and the production of its oxidized derivatives, known as oxysterols, contribute significantly to immunosuppressive conditions within tumors. In melanoma, oxysterols such as 27-hydroxycholesterol (27-HC) activate liver X receptors (LXRs) on immune cells, leading to the recruitment of MDSCs and neutrophils into the TME (74). This recruitment suppresses effective anti-tumor immune responses, creating an environment conducive to tumor survival. Additionally, oxysterols inhibit dendritic cell migration by downregulating CCR7 expression, preventing these antigen-presenting cells from effectively initiating cytotoxic T cell responses (75). Cholesterol accumulation in melanoma also contributes to T cell exhaustion, a key factor in immune evasion. Increased cholesterol levels within CD8⁺ T cells induce mitochondrial dysfunction and upregulate inhibitory receptors such as PD-1 and TIM-3, reducing the cytotoxic function of these cells. This exhaustion severely limits the effectiveness of immune checkpoint blockade therapies (76).