Immunometabolic Targets in CD8+ T Cells within the Tumor Microenvironment of Hepatocellular Carcinoma

Abstract

Background: CD8⁺ T cells are critical for the oncogenesis and progression of the hepatocellular carcinoma (HCC) tumor microenvironment, receiving antigen signals from antigen-presenting cells and directly contributing to antitumor responses.

Summary: CD8⁺ T cells mediate immunogenic cell death, facilitate immune signal transmission, and play a significant role in various treatments, including surgery, transarterial chemoembolization, and immunotherapy. Extensive research on the role of CD8⁺ T cells within the HCC microenvironment has shown considerable progress. Immunometabolic targets on CD8⁺ T cells have demonstrated potential in combination with immunotherapies for HCC; however, they have not yet reached the clinical trial stage.

Key messages: This review provides a comprehensive overview of recent research on immune and immunometabolic targets of CD8⁺ T cells within the HCC microenvironment. By highlighting advances and potential mechanisms, this review aims to support the development of effective clinical strategies in this field.

Keywords: CD8+ T cell; Hepatocellular carcinoma; Immunotherapy; Mammalian target of rapamycin; Metabolism; Tumor microenvironment.

Fig. 1.

Exhaustion of CD8⁺ T cells in the HCC Microenvironment. Antigen-presenting cells (APCs) activate tumoricidal immune cells by presenting antigen signals. Only major histocompatibility complex class I (MHC I) molecules presented by dendritic cells (DCs) can effectively activate CD8⁺ T cells, prompting their proliferation and differentiation into memory T cells (Tm) or effector T cells (Teff). Effector T cells exert antitumor effects through cytotoxic mediators, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). However, prolonged immune stimulation reduces Teff cell longevity and allows tumor cells to evade immune surveillance. To adapt to the tumor microenvironment (TME), tumor-infiltrating CD8⁺ T cells upregulate immune checkpoints and adopt an immunosuppressive phenotype known as exhausted CD8⁺ T cells. Programmed cell death protein 1 (PD-1) is the first immune checkpoint observed in progenitor exhausted CD8⁺ T cells, indicating partial immune suppression. As exhaustion progresses, terminally exhausted CD8⁺ T cells express T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) in combination with galectin-9 (Gal-9), further inhibiting T-cell receptor (TCR) signaling and antitumor immunity. DC, dendritic cell; Gal-9, Galectin-9; HCC, hepatocellular carcinoma; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; PD-1, programmed cell death 1; TAM, tumor-associated macrophage; TCR, T cell receptor; Teff, effector T cells; TIM-3, T cell immunoglobulin and mucin domain-containing protein 3; Tm, memory T cells.

Fig. 2.

Glucose and glutamine competition in the HCC microenvironment. In the tumor microenvironment (TME), glucose serves as the primary energy source for cellular metabolism. Hepatocellular carcinoma (HCC) tumor cells dominate glucose uptake, consuming the largest share to fuel rapid proliferation. While glycolysis generates substantial ATP for these tumor cells, they also exhibit high glutamine uptake to meet additional metabolic needs. Following tumor cells, myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) prioritize glucose uptake and show significant glutamine uptake as well. Regardless of initial substrates, all metabolic pathways converge at the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), which generate substantial reactive oxygen species (ROS) as nutrient metabolism byproducts. Due to a comparatively weaker autophagy system, CD8⁺ T cells are more susceptible to ROS-induced oxidative stress than tumor cells, MDSCs, and TAMs. The thickness of the arrows indicates the magnitude of glucose and glutamine uptake flux. HCC, hepatocellular carcinoma; MDSC, myeloid-derived suppressor cell; ROS, reactive oxygen species; TAM, tumor-associated macrophage.

Fig. 3.

Metabolic reprogramming of CD8⁺ T Cells in the TME. The energetic metabolism of CD8⁺ T cells, centered around the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), depends on mitochondrial function. Due to poor glucose uptake and hypoxic conditions in the tumor microenvironment (TME), CD8⁺ T cells upregulate glycolytic pathways to meet ATP demands, leading to increased lactate secretion into the TME. The fatty acid oxidation (FAO) pathway is enhanced to offset the energy deficit caused by exhaustion signaling and the abundance of free fatty acids in the TME. Concurrently, CD8⁺ T cells catabolize amino acids such as glutamine and branched-chain amino acids (BCAAs) into acetyl-CoA and α-ketoglutarate (α-KG) to support the TCA cycle. However, intracellular oxidative reactions produce excessive reactive oxygen species (ROS), resulting in mitochondrial stress. NADPH and glutathione (GSH) act as primary intracellular antioxidants. CD8⁺ T cells convert extracellular cysteine and methionine into cysteine, a substrate for GSH synthesis. Additionally, glucose-6-phosphate (G-6-P) generated via glycolysis enhances NADPH, production through the pentose phosphate pathway (PPP), helping neutralize ROS. α-KG, alpha-ketoglutarate; BCAA, branched-chain amino acid; CoA, coenzyme A; Gclc, glutamate cysteine ligase; GSH, glutathione; G-6-P, glucose-6-phosphate; MTA, 5’-methylthioadenosine; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PD, programmed cell death; PPP, pentose phosphate pathway; ROS, reactive oxygen species; SAM, S-adenosylmethionine; Slc, solute carrier; TCA, tricarboxylic acid cycle.

Fig. 4.

Roles of amino acids in energy supply, antioxidation, and biosynthesis in CD8⁺ T cells. amino acids play critical roles in energy metabolism, antioxidation, and biosynthesis throughout the lifecycle of CD8⁺ T cells. They serve as fundamental building blocks for proteins that form cellular structures and enzymes essential for cell growth. The metabolism of L-arginine, glutamine, and methionine provides carbon, nitrogen, and methyl groups necessary for various biosynthetic pathways. The tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) are the primary sources of adenosine triphosphate (ATP) for cellular activities. Glutamine enters the TCA cycle alongside leucine through intermediate metabolites like α-ketoglutarate (α-KG) and acetyl-CoA. Additionally, L-arginine is converted into creatine, serving as an alternative energy reservoir. Glutamine also generates glutamate, which combines with cysteine and glycine to form glutathione (GSH), an antioxidant that neutralizes reactive oxygen species (ROS) produced by cellular oxidative reactions. Nicotinamide adenine dinucleotide phosphate (NADPH), produced via glycine-related one-carbon metabolism, acts as another crucial antioxidant defending against ROS. α-KG, alpha-ketoglutarate; CoA, coenzyme A; GSH, glutathione; NADPH, reduced nicotinamide adenine dinucleotide phosphate.

Fig. 5.

mTOR complexes and metabolic regulation in CD8⁺ T cells. The mechanistic target of rapamycin (mTOR) forms complexes with defining subunits – Raptor for mTOR complex 1 (mTORC1) or Rictor/Sin1 for mTOR complex 2 (mTORC2) – along with the stabilizing protein mammalian lethal with Sec13 protein 8 to coordinate metabolic processes. mTORC1 is activated by mTORC2 and extracellular signal-mediated AKT phosphorylation, subsequently regulating downstream targets. In metabolic regulatory pathways, mTORC1 upregulates lipid synthesis, glutamine uptake, and glycolysis while suppressing the tricarboxylic acid (TCA) cycle and fatty acid oxidation (FAO). This metabolic reprogramming promotes the differentiation of CD8⁺ T cells into effector T cells rather than memory or exhausted phenotypes. Meanwhile, mTORC1 and AKT reciprocally regulate the tuberous sclerosis complex (TSC), which inhibits Ras homolog enriched in brain (Rheb), the activator of mTORC1, forming a negative feedback loop. Additionally, nutrients like amino acids activate mTORC1 through Rheb and the GTPase-activating protein toward Rags 1/2 signaling pathways. However, the mechanisms by which mTORC2 and metabolic reprogramming regulate T-cell functions remain to be fully elucidated. AKT, serine/threonine protein kinase B; FAO, fatty acid beta-oxidation; FOXO1, forkhead box protein O1; GATOR, Gap activity toward Rags; HIF-1α, hypoxia inducible factor-1 alpha; mLST8, mammalian lethal with Sec13 protein 8; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; OXPHOS, oxidative phosphorylation; Rheb, Ras homolog enriched in brain; SREBP, sterol regulatory element binding protein; S6K, ribosomaiprotein S6 kinase; TCR, T cell receptor; Tm, memory T cells; TSC, tuberous sclerosis complex protein complex; Teff, effector T cells.