Regulation of CD8+ T cells by lipid metabolism in cancer progression

Abstract

Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.

Keywords: CD8+T cells; Immunotherapy; Lipid metabolism; Mitochondria; Oxidative phosphorylation.

Fig. 1

Lipid metabolism in cells. This figure illustrates the pathways of lipid metabolism in cells. Fatty acids (FAs) enter the cell through lipid translocases such as CD36, FABPs, and FATPs or via passive diffusion. Low-density lipoprotein (LDL) enters the cell through low-density lipoprotein receptors (LDLRs). Inside the cell, FAs are esterified to acyl-CoAs by ACSL enzymes for metabolism. Acyl-CoAs destined for catabolism are transported into mitochondria through CPTs to undergo fatty acid oxidation (FAO). Acetyl-CoA produced from FAO enters the TCA cycle, with electrons from NADH and FADH2 used in oxidative phosphorylation (OXPHOS) for ATP generation and oxygen respiration. Citrate from the TCA cycle can exit the mitochondria and be converted into acetyl-CoA by ACLY, initiating de novo fatty acid synthesis. Acetyl-CoA can be used by HMGCR for cholesterol synthesis or by FASN, along with malonyl-CoA, to produce palmitate, which is then activated to palmitoyl-CoA. Activated palmitate can be desaturated by SCDs to create monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs) and elongated by ELOVLs. Fatty acyl-CoAs combine with glycerol to form monoacylglycerols (MAGs), diacylglycerols (DAGs), and finally triacylglycerols (TAGs) via DGAT. TAGs are stored in lipid droplets, and lipases release FAs from TAGs, DAGs, and MAGs through hydrolysis. The figure also highlights the main transcriptional programs for lipid catabolism (PPARs) and anabolism (SREBPs)

Fig. 2

Metabolic features of different CD8+ T cells. This figure depicts the distinct metabolic characteristics of CD8+ T cells in different states. Naïve CD8+ T cells are metabolically quiescent and take up minimal amounts of glucose and lipids to maintain their slow metabolic activities. These cells primarily derive their energy from the TCA cycle, with OXPHOS playing a significant role. Upon activation, effector CD8+ T cells become highly metabolically active and increase their mitochondrial activities. To meet the increased energy demands for proliferation and effector functions, these cells increase their uptake of glucose and lipids. Effector CD8+ T cells rely primarily on glycolysis and OXPHOS for energy production, sustaining their rapid growth and cytotoxic activities. In the tumor microenvironment, CD8+ T cells often become exhausted, resulting in impaired metabolism. Exhausted CD8+ T cells have reduced activities in both the TCA cycle and OXPHOS, relying predominantly on FAO to meet their energy needs

Fig. 3

Effects of lipid metabolism on mitochondria in tumor-infiltrating CD8+ T cells. This figure shows how lipid metabolism impacts mitochondrial function in tumor-infiltrating CD8+ T cells through various mechanisms. A Lipid accumulation. Tumor-infiltrating CD8+ T cells upregulate CD36 and LDLR to increase lipid uptake. Increased ACC activity leads to the formation of lipid droplets, whereas increased ACADVL expression reduces the levels of LCFAs and VLCFAs, decreasing lipotoxicity. B Shifts in energy metabolism. The IL-9/STAT3/CPT1 axis shifts energy metabolism in tumor-infiltrating CD8+ T cells from glycolysis/OXPHOS to FAO, increasing cytotoxicity. PPARα agonists activate PPARα to increase FAO. C Disruptions in mitochondrial dynamics. Akt inhibits PGC-1α, suppressing mitochondrial biogenesis. Increased MERCs in tumor-infiltrating CD8+ T cells promote memory T-cell formation. D Increased ROS production and cell death. Nrf2 or SOD2 inhibits ROS production, reducing lipid peroxidation, apoptosis, and ferroptosis in tumor-infiltrating CD8+ T cells

Fig. 4

Systemic factors regulating lipid metabolism and antitumor immunity. This figure represents several systemic factors that regulate lipid metabolism and influence CD8+ T-cell-mediated antitumor immunity, including a high-fat diet, obesity, aging, cachexia, circadian rhythms, stress, exercise, and other unknown factors. These factors modulate lipid metabolism in the body, thereby affecting the immune response to tumors