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Review
. 2024 Feb;25(2):471-488.
doi: 10.1038/s44319-023-00038-w. Epub 2024 Jan 12.

Immunosurveillance encounters cancer metabolism

Yu-Ming Chuang #  1   2 , Sheue-Fen Tzeng #  3 , Ping-Chih Ho  4   5 , Chin-Hsien Tsai  6   7
Affiliations
Review

Immunosurveillance encounters cancer metabolism

Yu-Ming Chuang et al. EMBO Rep. 2024 Feb.

Abstract

Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.

Keywords: Cancer Evolution; Immunoediting; Immunometabolism.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Mechanisms of metabolic tumor immune evasion.
During cancer progression, tumor cells and tumor-infiltrating lymphocytes (TILs), including CD8+ T cells, regulatory T cells (Tregs), and natural killer (NK) cells, rewire their metabolic programs in response to microenvironmental stress, such as nutrient deprivation and hypoxia. The metabolic interaction between tumor cells and diverse immune cells in and around solid tumors orchestrates the immunosuppressive TME and restrains host anti-tumor immunity. As a feedforward response to a stressful microenvironment, cancer cells acquired different metabolic adaption and interaction mechanisms to evade immune surveillance. It is also likely that harnessing the adaptive and innate immune response might bring greater rewards in cancer therapy. (A) Metabolic transitions can cause effector lymphocytes to become exhausted and dysfunctional, which in turn affects their differentiation. NK and T cells rely on glycolysis to maintain their effector function and viability. Proliferating tumor cells with elevated glycolysis may affect MHC class I and PD-L1 protein expression levels and compete with surrounding immune cells for glucose. This competition leads to glucose deprivation and elevated lactate levels, which impair the effector function of NK and CD8+ T cells but become beneficial for the suppressive activity of Tregs. (B) Cells metabolize nutrients such as glucose, amino acids, and fatty acids to produce various metabolites, like ATP, acetyl-CoA, NAD+, SAM, α-KG, fumarate, and succinate. These metabolites function as substrates or cofactors for modifying proteins and chromatin. Histone acetyltransferases (HATs) catalyze histone acetylation, while lysine deacetylases (HDAC and SIRT) mediate the reverse reaction. Glycolysis, fatty acid metabolism, and TCA cycle contribute to acetylation modification. The production of lactate generates lactyl-CoA, which contributes a lactyl group to lysine residues of histone proteins, creating a novel modification called lactylation. Succinyl-CoA, the primary substrate for succinylation, is derived from the TCA cycle, and KAT2A, CPT1A, and SIRT5 mediate the opposite reaction. AMPK is required for histone phosphorylation, depending on the ATP: AMP ratio. Chromatin methylation is linked to the folate cycle and the methionine cycle. Succinate, fumarate, and 2-HG inhibit KDMs and TETs, which catalyze demethylation in an α-KG-dependent manner. Additionally, NAD+ and NADH transitions lead to epigenetic modifications such as acetylation and succinylation. (C) Certain transcription factors, as well as oncogenic signaling pathways such as MYC, KRAS, AKT, and AMPK, are responsible for regulating the expression of immune checkpoint molecules like CD47 and PD-L1 as well as glycolysis-related genes, which, in turn, lead to immune evasion. Additionally, metabolites can also directly impact the expression of immunosuppressive molecules. For instance, succinate can activate PI3K-HIF1 signaling and promote M2 polarization by binding to succinate receptors. (D) Distinct metabolic preferences have been observed among tumor-infiltrating lymphocytes (TILs), which greatly impact their function and overall status. The maintenance of suppressive function in Tregs and M2 macrophages relies heavily on oxidative phosphorylation (OXPHOS) and fatty acid (FA) oxidation, facilitated by fatty acid transporters like CD36. The pro-tumorigenic phenotype of macrophages is also attributed to mincle-dependent β-glucosylceramide efflux. In contrast, the presence of fatty acids in the tumor microenvironment impairs the effector function and viability of intratumoral CD8 T cells. (E) The extent to which a 2-oxoglutarate-dependent dioxygenase (2OGDD) is suppressed by hypoxia depends on several factors, such as its expression level, oxygen affinity, and sensitivity to succinate and L-2HG inhibition. Hypoxia decreases the activity of hypoxia-sensitive 2OGDD, including EGLN proline hydroxylases. This inhibition of EGLN leads to the activation of HIF transcriptional activity. Moreover, hypoxia upregulates HIF target genes, including lactate dehydrogenase (LDH) and 2OGDD subsets. LDH generates L-2HG, which is potentiated by hypoxia and cellular acidosis, thereby accumulating high level of L-2HG. In certain types of cells, severe hypoxia may dysregulate the tricarboxylic acid (TCA) cycle, resulting in increased succinate production. Both succinate and L-2HG, which build up under hypoxic conditions, inhibit the function of 2OGDD. KSUCC Succinylated Lysine, FA fatty acid, FAO fatty acid oxidation, TAM tumor-associated macrophage, 2OG 2-oxoglutarate, HRE HIF-responsive element.
Figure 2
Figure 2. Metabolic plasticity in metastasis.
Cells undergo EMT to increase mobility, travel in circulation, and develop metastases, which can be regulated by metabolic activity. Metastasis involves rearranging the cytoskeleton and releasing enzymes that promote glycolysis for proliferation. Certain metabolites, such as fumarate, succinate, and fatty acid, act as signaling molecules that support EMT (left panel). Once detached, cancer cells also produce mitochondrial ROS, which promotes EMT and metastatic potential. When cancer cells are circulating (center panel), they may die due to oxidative stress, but those that survive have a metabolic advantage, which can be promoted in combination of neutrophils. CTCs increase NADPH production and lactate uptake, which boosts their antioxidant capacity. Once cancer cells reach the metastatic site (right panel), they must alter the tumor microenvironment to suppress immune surveillance, which can be done metabolically by facilitating TAM polarization and effector T cell dysfunction. Additionally, cytokines and metabolites likely influence metastatic niche development (e.g., collagen hydroxylation), cancer cell dormancy, and cell proliferation. Thus, the metabolic cascade plays a critical role in this process and may offer a therapeutic vulnerability for treating metastatic cancer.
Figure 3
Figure 3. Immune cell-guided metabolic reprogramming leads to immune evasion.
During immunosurveillance, a two-way communication occurs between tumor cells and infiltrating immune cells through cytokines or metabolites, controlling immune evasion. Multiple metabolic features contribute to an immune suppressive TME, such as adenosine expression, lactate generation from robust glycolysis, competition for glucose, and fatty acid production. IL4 and IL13 production in Th2 and IFNγ expression from CD8+ T cells sculpt the cancer cell immunogenicity by reprograming metabolism via epigenetic control (Dey et al, ; Li et al, ; Tsai et al, 2023). Hence, a metabolic immunoediting process facilitates cancer progression and contributes to escape from immune surveillance by suppressing T cell effector function and promoting survival and function of regulatory T cells (Tregs). The highlighted targets in red and bold represent potential metabolic targets that could be used for clinical cancer therapy. Green lines represent potential pathways for metabolic reprogramming during immune evasion.
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