Introduction

Metabolic reprogramming has emerged as a critical feature of cancer. To adapt to the hypoxic and nutrient-poor microenvironment, in addition to increasing glucose uptake and aerobic glycolysis, tumor cells also undergo lipid metabolism reprogramming to enhance their biological behaviors [1]. This is characterized by increased lipid uptake, lipid synthesis, fatty acid oxidation (FAO), and lipid storage. Mounting evidence demonstrated that lipids play a critical role in cancer progression by serving as energy sources, membrane structures, signaling molecules (including bioactive lipids like S1P, PGE2, and LPA), and even causing epigenetic modifications through fatty acylation of key molecules [2, 3]. Mechanically, alterations in lipid metabolic phenotype in tumor cells are directly driven by continuous oncogenic events and extracellular tumor microenvironment (TME) factors such as hypoxia, acidosis, and nutritional alterations [4, 5].

In addition to supporting tumor development, lipid metabolic reprogramming also modifies the TME by influencing the recruitment, activation, and function of immune cells and stromal cells. Tumor cells and cells in TME interact with each other and form a reciprocal entity [6]. On one hand, tumor cells can actively modify the TME by secreting signaling molecules and metabolites, which affect the functions of cancer-associated fibroblasts (CAFs) and immune cells in TME [6]. On the other hand, lipid metabolic reprogramming, an adaptive change in cells within the TME, manifests as increased lipid uptake and accumulation, or FAO, driving the TME toward an immunosuppressive phenotype supporting tumor progression [7]. For example, upregulated lipid uptake and FAO increase lipid metabolic levels in regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), facilitating their immunosuppressive function [8,9,10]. Moreover, upregulation of CD36 in CD8+ T cells leads to excessive lipid accumulation, which impairs secretion of anti-tumor factors such as IFN-γ and TNF-α, ultimately suppressing their anti-tumor efficacy [11, 12]. Similarly, upregulation of CD36 in natural killer (NK) cells also impairs their tumor-killing activity through intracellular lipid accumulation. Studies have suggested that blocking lipid uptake via inhibition of CD36 on cytotoxic CD8+ T cells or Tregs enhances anti-tumor immune responses [8, 11].

Given the critical role of lipids in cancer progression, targeting to lipid metabolism-related pathways offers new therapeutic opportunities for cancer. A large body of evidence shows that inhibitors targeting lipid uptake, lipogenesis, and FAO in tumor cells have shown significant therapeutic effects in various cancers [13,14,15]. Besides, modulating lipid metabolism in stromal cells and immune cells also provides a new choice for anti-tumor therapy. Moreover, it can be combined with chemotherapy and immunotherapy, providing a new comprehensive strategy for optimizing cancer treatment. This review aims to clarify the lipid metabolic landscape in tumor cells and TME cells, and summarize potential targets to offer clues for further research and clinical applications of targeting lipid metabolism in cancer.

Landscape and mechanisms of lipid metabolic reprogramming in cancer

Lipid metabolic reprogramming in cancer

Most lipid molecules in the human diet are triacylglycerols (TAGs) and cholesterol. After absorption, TAGs can be hydrolyzed into glycerol and fatty acids (FAs). Glycerol is then converted into glycerol-3-phosphate (G-3-P), which enters glycolysis. FAs can either be stored as the primary component of membrane synthesis or converted to acyl-CoA for β-oxidation to provide energy. In tumors, several steps of lipid metabolism show universal enhancement to maintain their biological progressions. This includes increased lipid uptake, synthesis, storage, and FAO. To delve deeper into these lipid metabolic alterations, the following section provides an in-depth analysis (Fig. 1).

Fig. 1
figure 1

Lipid metabolic reprogramming in cancer. Tumor cells enhance lipid metabolism by increasing exogenous lipid uptake and lipid synthesis, leading to increased intracellular lipid content. Upregulation of lipid transport proteins such as CD36, FATPs, FABPs, and LDLR increases lipid uptake. These upregulations increase intracellular SUFA, PUFA, and cholesterol levels. Meanwhile, endogenous lipid synthesis originates from citrate in the TCA cycle, as well as intracellular glutamine, lactate and acetate, leading to the synthesis of SFA and cholesterol. The process is catalyzed by key enzymes such as FASN and SCD. FAs in tumor cells are catalyzed by ACSL to form acyl-CoA, which is involved in the subsequent synthesis of intracellular phospholipids with bioactive lipids and FAO. Acyl-CoA facilitates the translocation of enzymes into mitochondria through CPT1, the key enzyme of FAO, participating in the production of acetyl-CoA, providing energy for the biological behavior of tumor cells. Excess lipids in tumor cells are stored in LD as CE and TAG. This storage significantly prevents LPO and attenuates its risk of mediating tumor cell death

Lipid uptake in cancer

The increase in intracellular lipid content can be achieved through two pathways: endogenous and exogenous pathways. Endogenous lipids are primarily produced through de novo lipogenesis (DNL), which utilizes acetyl-CoA as a substrate. Exogenous lipids require the involvement of transport molecules, including CD36, fatty acid transport protein family (FATPs/SLC27), and fatty acid-binding proteins (FABPs) [4]. Notably, recent studies have established a link between the overexpression of these transport molecules and the poor prognosis across various cancers. For instance, CD36 overexpression is associated with a poor prognosis in breast, ovarian, gastric, colorectal, and prostate cancer [15]. Moreover, FABPs have been found to contribute to the promotion of cervical cancer metastasis by increasing intracellular Fas [16], while knockdown of FABPs suppressed tumor progression in vivo by inhibiting lipid uptake in glioblastoma [17]. FATP members have been implicated in cancer initiation and progression in melanoma and breast cancer in multiple studies [18, 19].

Lipid synthesis in cancer

Although the exogenous lipid sources increase, cancer cells also activate DNL to respond to their high metabolic demands[2]. This pathway begins with acetyl-CoA, which can be mainly generated from citrate, a substrate in the TCA cycle during nutrient catabolism, via ATP-citrate lyase (ACLY). Besides, acetate conversion via acetyl-CoA synthetase (ACSS) is another pathway to produce acetyl-CoA for DNL. Acetyl-CoA is activated by acetyl-CoA carboxylases (ACCs) to form malonyl-CoA, which is further catalyzed by fatty acid synthase (FASN) to form saturated fatty acids (SFA), palmitate (C16:0). The resulting palmitate can be elongated by elongation of very-long-chain fatty acids gene family (ELOVLs) and desaturated by stearoyl-CoA desaturases (SCDs) or fatty acid desaturases (FADSs) to synthesize monounsaturated fatty acid (MUFA), such as oleic acid (OA) (C18:1) and palmitoleic acid (C16:1). Moreover, desaturation caused by ELOVLs and FADSs converts ingested polyunsaturated fatty acids (PUFAs) like linoleic acid (LA) (C18:2) and alpha-linolenic acid (ALA) (C18:3) into other PUFAs like arachidonic acid (AA) (C20:4) and adrenic acid (AdA) (C22:4) [20, 21]. Interestingly, overexpression or increased activity of ACLY has been correlated with the progression of various cancers [22]. ACSS is transcriptionally upregulated by SREBP, highly expressed in tumor cells, and plays a role in maintaining cancer cell growth under nutrient deficiency by catalyzing acetate [23]. FASN is commonly overexpressed in many epithelial and precancerous lesions and is associated with a high risk of cancer recurrence and mortality [24]. Inhibition of FASN can suppress breast cancer growth in the brain, highlighting its potential as a therapeutic target for metastasis in breast cancer [25]. SCD1 facilitates the formation of MUFAs, including OA, and its increased expression has been shown to promote the progression of cancers [26, 27].

In oncogenic processes, tumor cells utilize other metabolic substances in the microenvironment, such as glutamine and lactate, as sources of lipid synthesis. Glutamine dependence has been considered a metabolic hallmark of cancer cells. A growing body of evidence has shown that glutamine uptake and synthesis is upregulated in various cancers [28]. Cellular glutamine undergoes a transformation into α-ketoglutarate through the activation of glutaminase (GLS) and glutamate dehydrogenase (GLUD), ensuring the replenishment of vital metabolic intermediates within the TCA cycle. Subsequently, α- ketoglutarate is carboxylated by isocitrate dehydrogenase (IDH) to generate citrate [29]. In addition to glutamine, lactate is also an important source of TCA cycle intermediates and acetyl-CoA [30]. A recent study identified that lactate in the TME can reprogram lipid metabolism by increasing the expression of the genes involved, promoting tumor progression [31]. Notably, lactate promotes glutamine uptake and catabolism in oxidative cancer cells [32]. Therefore, utilizing glutamine and lactate to produce acetyl-CoA as a source of lipid synthesis is one of the important indirect ways for tumor cells to regulate lipid metabolism.

The synthesis of triacylglycerol (TAG) from long-chain fatty acids (LCFAs) derived from lipid intake and DNL involves a series of enzymatic reactions. Specifically, glycerol-3-phosphate acyltransferase (GPAT) catalyzes the combination of LCFAs with G-3-P to generate lysophosphatidic acid (LPA), which is a crucial intermediate in TAG synthesis. LPA is then converted to diacylglycerol (DAG) and subsequently to TAG via diacylglycerol acyltransferase (DGAT) [33]. Notably, DAG is also involved in compound lipid synthesis, such as cholesterol and phospholipids, which play critical roles in supporting key oncogenic functions and cancer hallmarks, and in regulating intercellular communication and immune responses [34].

Cholesterol, like other lipids, relies on acetyl-CoA for intracellular synthesis. Activating key enzymes in the mevalonate (MVA) synthesis pathway, such as HMG-CoA reductase (HMGCR), enables cholesterol biosynthesis. MVA is further modified to generate a variety of cholesterol for important biological processes such as membrane biosynthesis. Excess cholesterol is eliminated from the cell through ATP-binding cassette transporter A1 (ABCA1) [35]. In addition, low-density lipoproteins (LDLs) are taken up through membrane receptors (LDLRs), and high LDLRs levels promote LDL cholesterol-mediated breast cancer growth [36]. Reprogramming of cholesterol metabolism in tumors is mainly characterized by increased levels of intracellular cholesterol synthesis and abnormal metabolite accumulation [35]. This upregulation of cholesterol metabolism in both tumor cells and TME can promote oncogenic processes, such as tumor initiation, migration, and angiogenesis [37, 38].

Phospholipid (PL) synthesis, using DAG as a precursor, is enhanced in cancer, which regulates biological behaviors such as metastasis and drug resistance by modulating changes in membrane lipid composition and producing bioactive lipid second messengers [39]. Phosphatidylcholine (PC) is the predominant phospholipid in most cellular membranes. An increase in PC synthesis, along with elevated levels of choline cycle metabolites such as choline, phosphocholine (PCho), and glycerophosphocholine (GPC), has emerged as a significant hallmark of malignant transformation in tumors [40]. PC metabolic enzyme, choline kinase (ChoK), has been observed to be activated in various cancers [41]. Studies both in vitro and in vivo have shown that overexpression of ChoKα contributes to tumor progression, metastasis, and aggressiveness [42, 43].

In addition, PL catabolism is mediated by phospholipases (PLA2, C, and D), which can be recycled for PL biosynthesis and modulate various lipid-mediated signaling pathways promoting tumorigenesis. PL can also be hydrolyzed by PLC and PLD, producing DAG and phosphatidic acid (PA). This sustains the activity of key oncogenic signaling pathways involving PKC and mTOR [44]. Importantly, a significant portion of PL is hydrolyzed by PLA2, leading to the production of lysophosphatidylcholine (LPC) and AA. Subsequently, under catalysis of a series of enzymes, various lipid-derived mediators, including LPA, PGs, LTs, and S1P, are generated within tumor cells. LPC is catalyzed by lysophosphatidylcholine acyltransferases (LPCATs) to be reconverted into PC. Under the action of autotaxin (ATX), LPC is converted to LPA [45]. Similarly, AA participates in lipid mediator biosynthesis, producing prostaglandins (PGs) through cyclooxygenase (COX) and leukotrienes (LTs) through lipoxygenase (LOX). And sphingosine-1-phosphate (S1P) is also derived from sphingomyelin. These lipid-derived mediators are released extracellularly and act as crucial signaling molecules that mediate the crosstalk between the tumor and the TME for cancer progression [46].

Lipid storage in cancer

Increased uptake and endogenous synthesis of lipids in tumor cells lead to an increase in the cellular lipid pool. Acyl-CoA cholesterol acyltransferase (ACAT) converts free cholesterol to cholesteryl ester (CE) within the endoplasmic reticulum (ER) membrane, while excess intracellular FAs are ultimately converted into TAG by DGAT. These lipids are then stored as CE and TAG within lipid droplets (LD) in cells, reducing cell damage caused by peroxidation of free lipids within the cell [47, 48]. Lipids stored in LD can provide ATP response to metabolic stress by undergoing β-oxidation to produce acetyl-CoA. LDs serve as a critical reservoir of unsaturated FAs that cancer cells can use to maintain the function of cell membranes and organelles, particularly when there is an increased demand for lipids, such as during rapid oncogene-driven cell growth or a hypoxic environment [48]. Additionally, another key function of LDs is to protect cancer cells under ER stress and oxidative stress [49]. DGAT1, a key protein in lipid accumulation, promoting LDs formation and protecting cancer against lipid peroxidation, has been found to play indispensable oncogenic roles in melanoma and glioblastoma [50, 51].

Lipolysis in cancer

Degradation of TAG in LD can be initiated by adipose triglyceride lipase (ATGL), hydrolyzing TAG to produce DAG. DAG is then hydrolyzed by hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MAL) to release FFA. Given that lipid synthesis and LD accumulation are common metabolic characteristics of cancers, ATGL, the key enzyme for LD mobilization, is generally downregulated in most cancer cells [52]. Recent research suggests that enhanced ATGL expression exerts an anti-tumor effect in triple-negative breast cancer cells [53]. In hypoxic cancer cells, LD is significantly accumulated, which is resulted by the activation of hypoxia-inducible gene 2 (HIG2) to inhibit ATGL-mediated lipolysis [54, 55]. However, ATGL upregulation in tumor exhibits pro-tumor effects in some adipose-infiltrated cancers, including colorectal and breast cancer [56, 57]. In coculture systems, breast cancer cells exhibit increased proliferation and migration after acquiring FAs from adipocytes, which is dependent on the lipolysis induced by ATGL in both adipocytes and cancer cells [57]. Besides, ATGL also play a crucial role in the development of colon cancer driven by obesity [58]. These studies indicate that lipolysis acts as a double-edged sword in cancer progression, and the underlying mechanisms require further elucidation.

Lipid oxidation in cancer

As FAs uptake and storage increase, FAs catabolism in cancer cells is often enhanced. The survival and metastasis of cancer cells also rely on the uptake and consumption of FAs. FAO serves as an energy source for tumor cells under nutrient-deficient conditions. Carnitine palmitoyl transferase 1 (CPT1), the rate-limiting enzyme involved in mitochondrial FAO of LCFAs, mediates the entry of FAs into mitochondria. Once FAs enter the mitochondrial matrix, they are oxidized to generate acetyl-CoA, which enters the TCA cycle to produce ATP. The long-chain acyl-CoA synthase (ACSL) enzyme family plays an important role in FAO and lipids biosynthesis, facilitating the production of fatty acyl-CoA [59]. Tumors exhibit high FAO activity by upregulating CPT1A expression. Moreover, upregulation of CPT1A expression can promote EMT and stemness, leading to the invasive and metastatic capabilities of cancer cells [60, 61].

Lipid peroxidation (LPO) is prone to occur in PUFA-phospholipids (PUFA-PLs), resulting in the accumulation of lipid peroxidation within cells, which is caused by an imbalance in the ratio of intracellular PUFA to MUFA. This phenomenon is commonly associated with an increase in PUFA due to LD synthesis inhibition or a decrease in MUFA due to downregulation of enzyme activity involved in MUFA synthesis. LPO is significant in mediating ferroptosis and is often inhibited in progressing tumors [62, 63]. LDs, essential mediators of free unsaturated FA (especially PUFA) storage, regulate LPO and susceptibility to ferroptosis [64]. Upregulation of DGAT promotes LD synthesis in glioblastoma and gastric cancer cells. Inhibiting the formation of LDs by silencing DGATs can induce LPO and ferroptosis, thereby inhibiting cancer cell metastasis [50, 65]. Maintaining MUFA-phospholipid (MUFA-PL) levels in the cell membrane is critical for tumor cells to avoid ferroptosis. ASCL3, which is upregulated in various cancers, mainly catalyzes MUFA generation to form fatty acyl-CoA, promoting the synthesis of MUFA-PLs [59]. Furthermore, ACSL4 promotes the increase of membrane PUFA-PL levels by acting on PUFA, an essential therapeutic approach for tumor by increasing LPO and inducing ferroptosis [66]. Inhibition of the key enzyme SCD1 in gastrointestinal cancers reduces MUFA production, inducing ferroptosis and exerting anti-tumor effects [67, 68]. As research progresses, inducing the accumulation of lipid peroxides and promoting ferroptosis have become potential targets for anti-tumor therapy through lipid metabolism.

Oncogenic cues affecting tumor lipid metabolism

Activation of oncogenes and loss-function of tumor suppressor genes are the main causes of tumorigenesis. They also play an important role in reprogramming tumor metabolism by regulating lipid metabolic enzyme expression [4]. Sterol regulatory element-binding proteins (SREBPs) act as key upstream regulators of lipid metabolism. SREBP is a transcription factor that promotes DNL by upregulating key enzymes such as ACLY, FASN, and SCD, which are closely linked to tumor proliferation, apoptosis, and invasion [69]. Moreover, SREBP maintains intracellular cholesterol levels by inducing LDL receptor-mediated cholesterol uptake and inhibiting ABCA1-mediated cholesterol export in a mTORC1-dependent manner [70]. Downstream lipid reprogramming events are induced by SREBPs and mutations in oncogenes such as PI3K and MYC, as well as tumor suppressor genes such as p53 and PTEN (Fig. 2a).

Fig. 2
figure 2

Lipid metabolic alterations induced by oncogenic events and TME cues. Alterations in lipid metabolism in tumor cells are driven by oncogenic events and tumor environmental cues, such as hypoxia and nutritional deficiency conditions. a Activating mutations in oncogenes (such as MYC) and inactivation of tumor suppressor genes (such as p53 and PTEN) often occur in various tumor cells. Alterations in these genes subsequently upregulate the expression of key enzymes involved in lipid metabolism by regulating the PI3K-AKT-mTOR signaling pathway to activate transcriptional activity of SREBPs, or acting directly on key enzymes. As a consequence, lipid metabolism in tumor cells is enhanced. b TME encompasses various factors such as hypoxia, acidosis, and nutrient deficiency that promote tumorigenesis and cancer progression through reprogramming lipid metabolism in tumors. Lipid uptake, synthesis, and intracellular lipid accumulation are significantly upregulated in TME by activating key signaling pathways and enzymes

PI3K mutation

The dysregulation of the PI3K-AKT signaling pathway is a frequent occurrence in cancer and leads to metabolic reprogramming, where SREBPs play a crucial role as downstream regulatory targets. This pathway can be activated by various upstream signaling events, such as receptor tyrosine kinase (RTK) signaling or oncogenic mutations in PIK3CA [71]. By increasing lipid synthesis, this pathway promotes the occurrence and progression of liver cancer [72, 73]. The tumor suppressor PTEN is a critical negative regulator of the PI3K/AKT pathway, and its mutation can also activate this pathway [74]. Research has demonstrated that the loss of PTEN and the activation of PI3K/AKT lead to LD synthesis, contributing to prostate cancer progression [75]. In xenograft mice models of PIK3CA mutant breast cancer and PTEN-deficient prostate cancer, the excessive activation of the PI3K-AKT-mTOR signaling protects cancer cells from LPO and ferroptosis by SREBP1/SCD1-mediated MUFA synthesis [69]. Similarly, recent studies have shown that aspirin inhibits mTOR/SREBP-1/SCD1-mediated MUFA production and induces ferroptosis in PIK3CA mutant colorectal cancer [76]. In summary, the PI3K-AKT signaling may prove to be a potential therapeutic strategy for treating cancer as a metabolic disease.

P53 mutation

TP53, which encodes the tumor suppressor p53, is a commonly mutated oncogene in human cancers. p53 can bind directly to the promoter region of SREBP-1 and transcriptionally inhibit its expression, affecting downstream expression of key enzymes (ACLY, FASN) involved in lipogenesis [77]. Additionally, p53 suppresses the pentose phosphate pathway (PPP), which decreases NADPH production required for lipid synthesis [78, 79]. In breast cancer, p53 mutants have been shown to promote cancer progression by increasing cholesterol synthesis through enzymes involved in upregulation of the mevalonate pathway, highlighting the potential to target this pathway for p53-mutated tumors [80]. Moreover, the expression of genes key to FA synthesis (FASN, ELOVL6, and SCD1) is increased in p53-mutated tumors, while p53 transcription induces CPT1, which increases FAO and reduces intracellular lipid accumulation [81].

MYC mutation

MYC, a commonly activated oncogene in tumors, is known to promote transcriptional activation of genes involved in cell cycle, cell growth, and metabolism [82]. In addition to activating SREBP1, MYC directly regulates the expression of key enzymes involved in FA synthesis, such as ACLY, ACC, FASN, and SCD1, which have been shown to drive tumorigenesis in hepatocellular carcinoma (HCC) [83,84,85]. MYC also cooperates with SREBP2 to upregulate HMGCR for cholesterol metabolic reprogramming, contributing to the malignant phenotypes of tumor cells [86, 87]. Moreover, MYC-driven cancer cells exhibit enhanced glutamine utilization, with increased expression of key glutamine-metabolizing enzymes, including GLS1 and GLUD1, as well as the transporter protein SLC1A5 [88]. This augmented glutamine catabolism results in mitochondrial metabolic reprogramming to accommodate the replenishment requirements of the TCA cycle, supplying substrates for DNL, thereby sustaining cell vitality and growth [89]. What’s more, breast cancer cells with MYC overexpression show increased dependence on FAO for bioenergetics. Inhibiting FAO markedly diminishes the energy metabolism of these cells, suggesting that targeting FAO could be a potential therapeutic strategy for breast cancer [90, 91].

Microenvironment factors affecting tumor lipid metabolism

Metabolic reprogramming of cancer cells is the result of a multifactorial process. Along with the activation of oncogenic signals caused by mutations in tumor cells, TME also plays a crucial role [92]. The TME encompasses various factors such as hypoxia, acidosis, and nutritional deficiencies, which promote tumor initiation and cancer progression by altering lipid metabolism in tumor cells (Fig. 2b).

Hypoxia

The rapid proliferation of solid tumors consumes a large amount of oxygen, leading to hypoxia as a typical feature of almost all TME [93]. The resulting hypoxia inhibits the pyruvate metabolic pathway of glucose, resulting in decreased citrate content in the TCA cycle. As citrate, the primary substrate for DNL, decreases, cancer cells turn to alternative carbon sources such as glutamate or acetate to produce acetyl-CoA for FA synthesis [2, 94]. Hypoxic tumor cells utilize glutamine and synthesize citrate under IDH1 catalysis, a process that relies on the expression of hypoxia-inducible factor (HIF1) [95, 96].

In addition to alterations in glucose metabolism, lipid metabolism also undergoes changes in hypoxic tumor cells. FA catabolism is dependent on oxygen, and tumor cells often inhibit FAO through various pathways. Hypoxia-activated HIF-1α and HIF-2α downregulate CPT-1 expression, which prevents FAs from entering the mitochondria for β-oxidation [97, 98]. As a result, FAs are redirected to LD storage, leading to increased lipid accumulation [99]. Additionally, HIF-1α upregulates FABPs expression in hypoxia, promoting FA uptake and lipid storage by regulating the expression of key enzymes involved in TAG synthesis [17, 100]. In clear cell renal cell carcinoma (ccRCC), hypoxia increases intracellular LD synthesis in a HIF-2α-dependent manner, which plays a crucial role in sustaining ER homeostasis and aggressive tumor behaviors [101]. Furthermore, HIF-1 upregulates the expression of low-density lipoprotein receptor-related protein 1 (LRP1) to promote lipoprotein endocytosis and the lipids storage in LDs, providing energy for cells during hypoxia [102, 103].

In summary, hypoxia induces genes involved in FA uptake, synthesis, and storage, leading to an overall increase in intracellular lipid content. The inhibition of key enzymes involved in FAO also supports lipid accumulation under hypoxia, and the accumulation of lipids in LDs helps sustain malignant behaviors of tumors [104].

Acidosis

TME is characterized by hypoxia and acidosis, both of which contribute to the metabolic reprogramming of tumor cells. Hypoxia results in lactate accumulation and H+ build-up, which alter the metabolic pathways of cancer cells and promote tumor metastasis [105]. Lactate activates the expression of the SLC1A5 and GLS1 to promote glutamine transport and catabolism, which provides substrates for the TCA cycle [32]. In the absence of acetyl-CoA produced by glycolysis in an acidic microenvironment, tumors rely heavily on FAO to generate energy by converting LCFAs into acetyl-CoA and producing NADH and FADH2 [106]. Interestingly, in tumor cells, an acidic environment upregulates CD36 and DGAT expression, promoting exogenous lipid uptake and the formation of LDs, thereby promoting metastasis through a TGF-β2-dependent mechanism [107]. Acidosis also stimulates fatty acid synthesis (FAS) and promotes hepatocarcinogenesis through activating the PI3K/AKT pathway, upregulating SCD1, and promoting its binding to peroxisome proliferator activated receptor-α (PPARα) [108]. Additionally, an acidic TME triggers SREBP2 activation in tumors, leading to upregulation of the downstream key enzyme ACSS2, which provides suitable growth conditions for cancer cells in the acidic environment. These findings suggest that an acidic TME and SREBP2 activation is associated with reduced overall survival of cancer patients [109].

Nutrient alteration

The rapid proliferation of tumors requires continuous acquisition of nutrients from the microenvironment, resulting in a nutrient-deficient TME[105, 110]. In obese phenotypes, changes in metabolic spectra within tumor tissues result in the accumulation of lipids in adipocytes within the TME [111, 112]. Consequently, tumor cells must alter their metabolic patterns to enhance the utilization of lipids for energy supply to sustain their biological behaviors. In fat-rich TME, cancer cells can produce cytokines that induce ATGL-dependent lipolysis in the adipocytes surrounding the tumor, resulting in the release of FFAs [113]. These FFAs are then taken up by cancer cells via CD36 and FABP3/4 to form LDs, which act as energy sources for malignant cells. Moreover, lipid transfer from adipocytes to cancer cells can also be facilitated by extracellular vesicles (EVs) [114, 115]. Adipocytes in the TME have been shown to act as metabolic regulators that promote the growth and survival of colon cancer cells [116]. When co-cultured with breast cancer cells, the consumption of TAGs within adipocytes is increased, which in turn transfers adipocyte-derived FFAs to breast cancer cells, increasing CPT1A levels and driving FA metabolism in cancer cells [117].

Dietary factors affecting tumor lipid metabolism

Dietary interventions can change metabolite levels in the TME, which may then affect cancer cell metabolism to alter tumor growth [118]. Obesity and excessive high-fat diets (HFDs) are associated with increased overall and cancer-specific mortality, especially among patients with breast, colon and uterine cancer [119]. Excessive adipose expansion during obesity causes adipose dysfunction and inflammation to increase systemic levels of proinflammatory factors. Cancer-associated adipocytes can enter the TME to enhance pro-tumor effects [120]. In obese mouse models, HFDs increase the number of LGR5+ intestinal stem cells and activate the lipid metabolism transcription factor PPARγ for their tumorigenic potential [121]. Importantly, fat-mediated inflammatory signaling and the immunosuppressive microenvironment in tumors are the main causes of tumor metastasis [122]. For instance, HFD-induced obesity leads to CD8+ T cell exhaustion by reducing the production of granzymes and cytokines (IFN-γ and TNF-α), ultimately accelerating tumor growth in mouse models [123, 124]. Moreover, HFDs can induce lipid accumulation in prostate tumors in a SPREP-dependent manner, facilitating metastasis in mouse models [125]. Similarly, chronic HFDs alter biological behaviors, including angiogenesis and proliferation, in breast cancer [126].

Notably, different types of dietary lipids exhibit heterogeneity in driving the biological behavior of tumors. A study demonstrates that dietary palmitic acid, in contrast to OA or LA, enhances metastasis in oral carcinomas and melanoma in mouse models [127]. SFA intake is associated with an enhanced MYC signaling and poorer outcome in prostate cancer patients [128]. OA can also favor survival and chemotherapy resistance in gastric cancer [129]. Mechanistically, HFDs raise systemic FA levels, including SFAs and unsaturated FAs, which further enhances FAO, producing enough energy to facilitate tumor progression. In addition, two essential FAs: ALA (ω-3 PUFA) and LA (ω-6 PUFA), play proinflammatory and anti-inflammatory roles in tumors, respectively. In patients with metastatic colorectal cancer, primary tumors exhibit significantly elevated levels of ω-6 PUFAs and reduced levels of ω-3 PUFAs compared to those in patients with non-metastatic cancer [130]. Dietary LA stimulates invasion and peritoneal metastasis of gastric cancer through COX-1-catalyzed lipid metabolism [131]. Consequently, alterations in dietary lipid consumption, adopting a low-fat eating pattern or increasing ω-3 PUFAs intake, may represent a selective anti-tumor therapy.

Landscape and mechanisms of lipid metabolic reprogramming in tme

As cancer progresses, the TME also undergoes lipid metabolic reprogramming. It is worth noting that tumor cells play a significant role in modifying TME (e.g., acidosis, lipid accumulation) by producing metabolites and lipid-related signaling molecules. This in turn influences metabolic patterns and immune phenotype of TME cells, resulting in immune microenvironment remodeling [65]. For example, the secretion of lipids by CAFs in the TME promotes tumor progression by directly supplying energy sources to tumor cells. What’s more, lipid metabolic reprogramming in CAFs also influences its own cytokine secretion function, which subsequently modulates the immune responses and promotes the formation of an immunosuppressive microenvironment. In addition, alterations in lipid metabolism patterns in immune cells also favor the construction of an immunosuppressive microenvironment, supporting tumor immune escape. Therefore, tumor progression is the result of a co-evolutionary process between tumor and TME. Moving forward, this section will focus on lipid metabolic alterations in TME cells and their interactions with tumor cells (Fig. 3).

Fig. 3
figure 3

Lipid metabolism landscape in TME. Tumor cells have the ability to educate TME cells into a pro-tumor phenotype by secreting metabolites and signaling molecules, such as cytokines and bioactive lipids, to TME, which further facilitates cancer progression. For instance, CAFs activated by tumor cells lead to increased levels of lipid synthesis, which serve as an essential energy source for tumor cells and induce the formation of an immunosuppressive microenvironment through secreting EVs and signaling molecules. Besides, tumor-infiltrating CD8+ T cells and NK cells also exhibited increased lipid uptake and FAO. Similarly, lipid accumulation in TAMs also regulates their polarization and functional phenotypes. Increased lipid uptake and FAO in immunosuppressive cells, such as Tregs and MDSCs, further enhanced their pro-tumor effects. Taken together, lipid metabolic reprogramming facilitates crosstalk between tumor cells and TME cells, fueling tumor cells and changing functional phenotypes of TME cells

Lipid metabolic reprogramming in CAFs

Cancer-associated fibroblasts (CAFs), an important stromal cell type in the TME, are activated by TGF-β and LPA signaling in TME [132, 133]. They synthesize and secrete lipids and bioactive lipid signaling molecules, playing an essential role in tumor metabolic alteration, proliferation, invasion and immune responses [134]. To adapt to the TME, CAFs undergo lipid metabolic reprogramming characterized by an increase in lipid synthesis, storage, and secretion by upregulating key enzymes like FASN and SCD [135, 136]. This constructs a microenvironment with lipid accumulation, leading to metabolic reprogramming and biological behavior enhances in tumors [115, 137].

In the hypoxic and nutrient-poor microenvironment, CAFs upregulate SCD1 expression via HIF-1α, increasing the abundance of lipids such as OA in CAFs, resulting in promoting lung cancer growth [136, 138]. Therefore, targeting SCD1 in CAFs could be a promising therapeutic strategy. Recent metabolomics studies have shown that CAF-derived lipids enhance lipid uptake in tumor cells, promoting peritoneal metastasis of colorectal cancer [139]. This phenomenon also depends on the upregulation of CPT1 in CAFs, which enhances FAO and shapes the TME for colorectal cancer metastasis [140].

In addition, CAFs shape lipid metabolism and biological behavior of tumor cells by secreting biologically active lipid molecules and EVs containing small molecules and lipid metabolites [20, 141, 142]. Overexpressed biologically active lipids, such as LPC, in CAFs can be released into the TME and absorbed by tumor cells to promote tumor proliferation and migration through intracellular lipid metabolic reprogramming [135, 143]. Mechanistically, LPC is hydrolyzed by LPA in cancer cells, activating the AKT signaling pathway [144]. PGE2 and S1P in CAFs also play vital roles in tumor progression in breast cancer and neuroblastoma [145,146,147]. What’s more, a high concentration of proinflammatory cytokines secreted by CAFs supernatant can induce upregulation of cholesterol metabolism in prostate cancer cells, promoting androgen receptor therapy resistance [148]. miR-522, secreted from CAF-derived EVs, inhibits ferroptosis in cancer by targeting arachidonate lipoxygenase 15 (ALOX15) and blocking LPO [149]. In breast cancer, CAF enhances their exogenous lipid uptake capacity by inducing upregulation of FATP1 [150, 151]. Similarly, CAFs promotes colon cancer cells to absorb lipids secreted from CAFs through CD36, thereby promoting cancer cell migration [135]. Lactate secreted by CAF induces lipid metabolic reprogramming in prostate cancer, leading to the LD formation and mobilization, concurrently enhancing tumor invasiveness [31]. These evidences suggest that the signaling molecules and metabolites secreted by CAFs play an essential role in tumor progression and may become promising therapeutic targets in future [152].

Overall, the crosstalk between CAFs and cancer cells is mediated by lipid metabolic reprogramming that contributes to cancer progression, metastasis, and therapeutic resistance. Moreover, recent studies have shown that lipid metabolic reprogramming of CAFs also plays an important role in remodeling the tumor immune microenvironment. For example, CD36+ CAFs recruit MDSCs through upregulating MIF expression, thus promoting immune escape in HCC. Inhibitors targeting to CD36 can restore the anti-tumor immune response in HCC and synergistically enhance the anti-tumor effect of anti-PD-1 therapy [153].

Lipid metabolic reprogramming in immune cells

Lipids are critical metabolites that support the biological activities of immune cells. Under normal conditions, immune cells with anti-tumor activity, such as effector CD8+ T cells, NK cells, and M1 macrophages, depend on glycolysis for their maturation and function, whereas immune-regulatory cells such as Tregs, M2 macrophages, and MDSCs rely on FAO to exert their tumor immune suppression effects [115]. When tumors occur, lipid metabolism of tumor cells and stromal cells, such as adipocytes and CAFs, contributes significantly to the establishment of a TME characterized by low glucose and high lipid accumulation [115, 137, 154]. In such a TME, immune cells display increased immunosuppressive effects by regulating their lipid metabolism patterns, and subsequently promoting tumor progression [65]. For instance, lipid accumulation and enhanced FAO in TAMs contributed to its polarization to the M2 phenotype, which blocked anti-tumor T cell responses and supported the immunosuppressive function of T cells [155]. Increased uptake of oxidized lipids and enhanced lipid peroxidation in CD8+ tumor-infiltrating lymphocytes (TILs) lead to their immune dysfunction, whereas lipid peroxidation resolution restored the functionalities of CD8+ TILs in vivo [11] (Table 1).

Table 1 Lipid metabolism in immune cells

CD8 + T cells

CD8+ TILs are an important component of anti-tumor immune cells, but their cytotoxic effects change to an exhausted state as cancer progresses [156,157,158]. In response to the limited nutrients and glucose in the TME, CD8+ TILs experience a significant reduction in glycolytic activity. To sustain their anti-tumor functions, CD8+ TILs undergo metabolic adaptation and promote FAO as an alternative energy source [159, 160]. However, excessively elevated lipid metabolism can lead to lipid peroxidation and ROS accumulation within the cell, further impairing their anti-tumor effects [161] (Fig. 4a).

Fig. 4
figure 4

Mechanism of lipid metabolic reprogramming in immune cells. A hypoxic, glucose-deficient, lipid-rich TME often educates immune cells into an immunosuppressive and pro-tumor phenotype by reprogramming their lipid metabolism. Immune cells in the TME undergo lipid metabolism reprogramming by directly absorbing excess lipids in the TME or enhancing their own lipid uptake, synthesis, and oxidation. Overexpression of PD-1 and CD36 on CD8+ TILs promotes metabolic transition by activating STAT3 or PPARs, which results in enhanced FAO (a). In Tregs cells, lipid metabolism is enhanced by CD36-PPARβ signaling, AKT-mTORC1 signaling, and SREBPs-mediated overexpression of FASN (b). TAMs can use lipids directly in TME or uptake exosomes containing LCFAs. FAO in TAMs is also enhanced by CD36-PPARs signaling (c). In DCs, NK cells, and MDSCs, CD36-PPARs signaling also plays a critical role in modulating their lipid metabolism (df)

CD8+ TILs often undergo metabolic transitions to adapt to the hypoxia, glucose deficiency and lipid accumulation in the TME. This transition involves converting glycolysis to FAO, maximizing their activity to maintain their anti-tumor function. For instance, in a mouse model of obesity-associated breast cancer, CD8+ TILs downregulate glycolytic activity and enhance FAO [162]. Additionally, CD8+ T cells in MC38 colorectal cancer cell line and B16 melanoma cell line-bearing mice models show an FAO increase with the upregulation of CPT1 [163,164,211]. It has been well demonstrated that increased lipid uptake and FAO in MDSCs can promote its production of immune-suppressive cytokines that inhibit cytotoxic effects of CD8+ T cells [212] (Fig. 4f).

Bioactive lipid signaling factors in TME promotes the realization of immune cells function. Specifically, in breast and colon cancer, studies have identified PGE2 as a crucial factor in activating MDSCs in TME [Full size image

Advances in targeting lipid metabolism combined with chemotherapy and targeted therapy

As described above, the dysregulated lipid metabolism in tumor cells provides energy support for tumor progression, playing an essential role in membrane synthesis and signal transduction. This shift in lipid metabolism, including the lipid uptake from the extracellular microenvironment, increased lipogenesis, and the increase in intracellular LD storage, correlates with the metastatic potential of tumor cells [224], the acquisition of stem cell-like properties [225], and the development of resistance to cancer chemotherapy [226, 227]. This may interfere with chemotherapy and targeted therapy in tumors. Therefore, aberrant lipid metabolism has become a potential target for treating drug-resistant cancer. Combination therapy can sensitize tumor cells to drugs, demonstrating a therapeutic effect superior to monotherapy [227]. Combination therapy also compensates for the insufficient efficacy of single-target lipid metabolism inhibitors. A considerable amount of preclinical research and clinical trials are currently focusing on novel strategies to enhance therapeutic effects by combining targeted lipid metabolism therapy with conventional chemotherapy and targeted therapy, even radiotherapy (Fig. 5a; Table 2).

Table 2 Combining lipid-targeted therapies with chemotherapy and targeted therapy

Targeting lipid uptake

Tumor cells exhibit a propensity for lipid uptake to support biosynthesis, energy production, and lipid storage in LDs. Consequently, inhibiting lipid uptake has emerged as a promising therapeutic strategy in oncology. Considerable preclinical evidence suggests that targeting the fatty acid receptor CD36 can be effective against various types of cancer [4, 15, 228, 229]. Particularly, CD36-mediated metabolic reprogramming in breast cancer, has been linked to resistance to HER2-targeted therapies. Recent clinical studies have confirmed that higher CD36 expression correlates with poorer outcomes in early-stage HER2+ breast cancer patients undergoing trastuzumab-lapatinib therapy [230]. Furthermore, JC63.1C, an anti-CD36 monoclonal antibody, was found to resensitize lapatinib-resistant xenograft tumors to HER2-targeted therapy [231], providing a novel direction for combinatorial treatment strategies in breast cancer. In addition, studies in leukemia models showed that the FA6.152 monoclonal anti-CD36 or the CD36 inhibitor SSO, when used in conjunction with chemotherapy drugs such as Ara-C or doxorubicin, led to a significant extension in survival [232, 233]. In PDAC, CD36 siRNA notably increased the efficacy of gemcitabine treatment [234].

Inhibiting FABPs has also demonstrated promising anti-tumor effects. FABP5 inhibitors, namely SBFI-102/103, were identified as novel targets in prostate cancer and were shown to enhance the tumor-suppressing effects of paclitaxel [235, 236]. FABP4 inhibitor BMS309403, was also found to boost the efficacy of carboplatin by inhibiting tumor metastasis in in vivo ovarian cancer models [237]. In another study, a mouse model of melanoma showed that inhibiting FATP2, another critical lipid metabolism transporter, in PMN-MDSCs using lipofermata, led to enhanced tumor regression when combined with BRAF/MEK inhibitor [238]. Taken together, these findings suggest that targeting lipid uptake by inhibiting fatty acid transporters is a promising new strategy to overcome therapy resistance in cancer treatment.

Targeting lipid synthesis

Increased lipid synthesis, inclusive of fatty acids and cholesterol, is a characteristic feature of tumors. Consequently, targeting key enzymes in these pathways is emerging as a potential therapeutic strategy for cancer, particularly in conjunction with chemotherapy and targeted therapy. ACLY, a key enzyme in the production of acetyl-CoA, serving as a substrate for DNL, supports tumor growth and confers resistance to vemurafenib in melanoma treatment. In tumor-bearing mice model, although vemurafenib exerted minimal effects on tumor growth, the combination of SB-204990 and vemurafenib exhibited a significantly more suppressive effect [239]. Similarly, in vitro results suggested that combining SB-204990 could be an effective strategy for treating cisplatin-resistant ovarian cancer [240]. In addition, ACCs, which catalyze the conversion of acetyl-CoA to malonyl-CoA, the initial step in fatty acid synthesis, are upregulated in cetuximab-treated head and neck squamous cell carcinoma (HNSCC) by the continuously activated AMPK pathway, suggesting a possible mechanism refers to the cetuximab resistance. A combination of cetuximab and TOFA, an ACC inhibitor, resulted in notable growth inhibition of cetuximab-resistant HNSCC xenografts in vivo [241]. Another ACC inhibitor, ND-646, when combined with carboplatin, could also significantly inhibit tumor growth in preclinical non-small cell lung cancer (NSCLC) models [242]. Similarly, the combination of sorafenib and a liver-specific ACC inhibitor (ND-654) effectively decreased tumor proliferation in vivo [243]. However, clinical trials assessing the efficacy of targeting ACC in tumors are currently scarce. Recent clinical trials have supported the use of an ACC inhibitor (Firsocostat) for treating nonalcoholic steatohepatitis (NCT02856555, NCT03987074) [244].

Palmitic acid synthesis, another rate-limiting step in DNL, is facilitated by FASN. Deregulation in the expression and activity of FASN carries significant implications for therapeutic response. FASN inhibitors, such as the anti-obesity drug Orlistat, have shown significant anti-tumor effects in various cancers [13]. Recent studies have underscored the efficacy of combining FASN inhibitors with other treatment strategies. Preclinical evidence suggests Orlistat's ability to reverse sorafenib resistance in HCC, thus illuminating new avenues for combined HCC treatment [245, 246]. Moreover, in prostate cancer, the combination of Orlistat and radiotherapy significantly reduces the activity of the NF-κB pathway, and inhibits cancer progression [247]. Preclinical research on pancreatic cancer, NSCLC, and ovarian cancer has shown that combining Orlistat with chemotherapy and targeted treatment significantly enhances anti-tumor effects [248,249,250]. Despite Orlistat being an FDA-approved therapy, there are currently no registered clinical trials examining its role in cancer. Another FASN inhibitor, TVB-3664, exhibits synergistic therapeutic effects when combined with TKI, as shown in an HCC mouse model [251]. A separate in vivo study using a lung adenocarcinoma xenograft model demonstrated the anti-tumor effects of combining TVB-3664 with a KRAS inhibitor [252]. The PI3K pathway, frequently hyperactive in tumor, plays crucial roles in both malignant and immune cells. The co-administration of the PI3K inhibitor (CYH33) with the FASN inhibitor (C75) has been found to synergistically inhibit tumor growth while enhancing host immunity [253]. Other FASN inhibitors like TVB-3166, Fasnall, and AZ12756122 also promote enhanced anti-tumor effects in combination therapies [254,

Availability of data and materials

Not applicable.

Abbreviations

FAO:

Fatty acid oxidation

TME:

Tumor microenvironment

CAFs:

Cancer-associated fibroblasts

Tregs:

Regulatory T cells

TAMs:

Tumor-associated macrophages

MDSCs:

Myeloid-derived suppressor cells

NK cells:

Natural killer cells

TAG:

Triacylglycerols

FA:

Fatty acid

DNL:

De novo lipogenesis

PL:

Phospholipid

FATP:

Fatty acid transport protein

FABP:

Fatty acid-binding protein

ACLY:

ATP-citrate lyase

ACSS:

Acetyl-CoA synthetase

ACC:

Acetyl-CoA carboxylases

FASN:

Fatty acid synthase

SFA:

Saturated fatty acid

MUFA:

Monounsaturated fatty acid

PUFA:

Polyunsaturated fatty acid

ELOVLs:

Elongation of very-long-chain fatty acids gene family

SCD:

Stearoyl-CoA desaturase

FADS:

Fatty acid desaturase

OA:

Oleic acid

LA:

Linoleic acid

ALA:

Alpha-linolenic acid

AA:

Arachidonic acid

AdA:

Adrenic acid

GLS:

Glutaminase

GLUD:

Glutamate dehydrogenase

IDH:

Isocitrate dehydrogenase

LCFA:

Long-chain fatty acid

GPAT:

Glycerol-3-phosphate acyltransferase

LPA:

Lysophosphatidic acid

DAG:

Diacylglycerol

DGAT:

Diacylglycerol acyltransferase

MVA:

Mevalonate

HMGCR:

HMG-CoA reductase

ABCA1:

ATP-binding cassette transporter A1

LDLR:

Low-density lipoprotein receptor

PC:

Phosphatidylcholine

PCho:

Phosphocholine

GPC:

Glycerophosphocholine

ChoK:

Choline kinase

PA:

Phosphatidic acid

LPC:

Lysophosphatidylcholine

LPCATs:

Lysophosphatidylcholine acyltransferase

ATX:

Autotaxin

PG:

Prostaglandin

COX:

Cyclooxygenase

LT:

Leukotriene

LOX:

Lipoxygenase

S1P:

Sphingosine-1-phosphate

ACAT:

Acyl-CoA cholesterol acyltransferase

ER:

Endoplasmic reticulum

LD:

Lipid droplet

ATGL:

Adipose triglyceride lipase

HSL:

Hormone-sensitive lipase

MAL:

Monoacylglycerol lipase

HIG2:

Hypoxia-inducible gene 2

CPT:

Carnitine palmitoyl transferase

ACSL:

The long-chain acyl-CoA synthase enzyme family

LPO:

Lipid peroxidation

PUFA-PL:

PUFA-phospholipid

MUFA-PL:

MUFA-phospholipid

SREBP:

Sterol regulatory element-binding protein

RTK:

Receptor tyrosine kinase

PPP:

Pentose phosphate pathway

HCC:

Hepatocellular carcinoma

HIF:

Hypoxia-inducible factor

ccRCC:

Clear cell renal cell carcinoma

LRP1:

Low-density lipoprotein receptor-related protein 1

FAS:

Fatty acid synthesis

PPAR:

Peroxisome proliferator activated receptor

HFD:

High-fat diet

EVs:

Extracellular vesicles

ALOX15:

Arachidonate lipoxygenase 15

CD8+ TILs:

CD8+ tumor-infiltrating lymphocytes

ox-LDL:

Oxidized low-density lipoprotein

PDAC:

Pancreatic ductal adenocarcinoma

GPX4:

Glutathione peroxidase 4

MARCO:

Macrophage receptor for collagenous structures

ICI:

Immune checkpoint inhibitor

M-MDSC:

Mononuclear MDSC

PMN-MDSC:

Polymorphonuclear MDSC

NSCLC:

Non-small cell lung cancer

HNSCC:

Neck squamous cell carcinoma

ADT:

Androgen deprivation therapy

AAD:

Antiangiogenic drug

ACT:

Adoptive cell transfer

PD-1:

Programmed cell death protein 1

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

PD-L1:

Programmed death-ligand 1

PGC-1α:

PPARγ coactivator 1-α

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This work is supported by grants from the National Natural Science Foundation of China (No.82173253), the Sichuan Province Science and Technology Support Program (No. 2022YFH0003 and No. 2023NSFSC1900), and the China Postdoctoral Science Foundation (No. 2022M712260). The funders had no role in the study design, data collection, analysis, decision to publish, or manuscript preparation.

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JLY and JW designed the outline. HRJ, JW, ZJW, and MJX participated in literature searches and drafted the manuscript. HRJ, JW, MJX, and BHX designed the figures and tables. JW, JLY, and KD supervised and edited the manuscript. All authors read and approved the final manuscript.

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**, HR., Wang, J., Wang, ZJ. et al. Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics. J Hematol Oncol 16, 103 (2023). https://doi.org/10.1186/s13045-023-01498-2

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