Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics

Abstract

Lipid metabolic reprogramming is an emerging hallmark of cancer. In order to sustain uncontrolled proliferation and survive in unfavorable environments that lack oxygen and nutrients, tumor cells undergo metabolic transformations to exploit various ways of acquiring lipid and increasing lipid oxidation. In addition, stromal cells and immune cells in the tumor microenvironment also undergo lipid metabolic reprogramming, which further affects tumor functional phenotypes and immune responses. Given that lipid metabolism plays a critical role in supporting cancer progression and remodeling the tumor microenvironment, targeting the lipid metabolism pathway could provide a novel approach to cancer treatment. This review seeks to: (1) clarify the overall landscape and mechanisms of lipid metabolic reprogramming in cancer, (2) summarize the lipid metabolic landscapes within stromal cells and immune cells in the tumor microenvironment, and clarify their roles in tumor progression, and (3) summarize potential therapeutic targets for lipid metabolism, and highlight the potential for combining such approaches with other anti-tumor therapies to provide new therapeutic opportunities for cancer patients.

Keywords: Cancer progression; Immune response; Lipid metabolism; Targeted therapy; Tumor microenvironment.

Fig. 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

Fig. 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

Fig. 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

Fig. 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 (d–f)

Fig. 5

Lipid-targeted therapy in combination with chemotherapy, targeted therapy and immunotherapy. Lipid metabolism reprogramming within tumors not only propels tumor progression and drug resistance, but also play a crucial role in shaping the immunosuppressive microenvironment. This provides a theoretical foundation for the comprehensive treatment strategies by targeting tumor lipid metabolism. In numerous preclinical studies, inhibitors of lipid metabolism have shown significant anti-tumor effects in combination with chemotherapy, targeted therapy and immunotherapy, which is superior to a single-target treatment. The targets of these inhibitors primarily include lipid uptake (CD36, FABPs, FATPs), lipid synthesis (ACLY, ACCs, FASN, SCDs, SERBP, HMGCR, ChoK, COX), FAO (CPT1, PPAR), and lipid storage in LDs (DGAT, ACAT). These findings provide valuable insights for optimizing therapeutic strategy for cancer patients by combination lipid-targeted therapy with present anti-tumor therapy