Metabolic regulation of the cancer-immunity cycle

Elevated tumor glycolysis and lactate production are robust suppressors of antitumor immunity in multiple cancer subtypes. Loss of mitochondrial function is a hallmark of CD8+ T cell exhaustion and might be a promising metabolic target for improving patient responses to CAR-T and/or ICB therapy, pending future investigations. IL4I1-driven tryptophan catabolism and aryl hydrocarbon receptor activation may constitute a resistance mechanism to ICB and/or IDO1 inhibitors across cancer subtypes. We propose that the metabolic profile of the TME promotes both initiation and disruption of the cancer-immunity cycle. Hence, targeting cellular metabolism in the TME may improve responsiveness to T cell-based immunotherapies. The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies. The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies. catabolic pathway that oxidizes glucose to pyruvate and subsequently reduces pyruvate to lactate. The latter step often occurs in anaerobic or hypoxic conditions, but under aerobic conditions in rapidly proliferating cells. programmed cell death caused by detachment of a cell from the extracellular matrix. target cyclin-dependent kinase 4 and 6; known for their ability to inhibit progression through the G1 phase of the cell cycle and, consequently, inhibit cell proliferation, including that of cancer cells. phenotype adopted by proliferating cells in response to stress or damage; characterized by an arrest in the cell cycle. T cell genetically engineered to increase antigen-specific T cell recognition of tumors. CARs contain an extracellular antigen-recognition domain and up to three intracellular signaling domains that activate T cells. Certain CAR T cells may be adoptively transferred to patients. molecules released by damage or dying cells that elicit immune responses through binding pattern recognition receptors. hydrolyzes nucleotide anhydride or ester bonds, producing nucleosides. catabolic pathway that promotes the oxidation of one molecule of glucose and produces two molecules of pyruvate. elevated number of somatic mutations in the genome of a cell. component of an inhibitory pathway intrinsic to the immune system that regulates the duration and amplitude of immune responses. antagonism of immune checkpoint function via therapeutic agents, mainly antibodies and inhibitors. ability of an organism to elicit an adaptive immune response. post-translational modification of proteins comprising the covalent addition of lactate to an amino acid residue (hitherto described for lysine) of a protein. Histone lactylation has been reported to epigenetically modulate gene expression. subset of genes expressed by macrophages that differentiate and acquire the so-called 'M2' immunosuppressive/wound-healing phenotype. tumors bearing inactivating mutations in genes encoding proteins involved in DNA mismatch repair. stimulated by mutations in one or more proto-oncogenes or tumor suppressor gene-encoded proteins. subset of exhausted CD8+T cells characterized by TCF-1+ and PD-1+ expression. These cells have stem cell-like properties (e.g., self-renewal capacity) and increased effector function compared with terminally exhausted CD8+ T cells. oxygen-containing molecules that are, or can give rise to, free radicals. ROS can damage and alter function of nucleotides, proteins, and membrane lipids. resemble those of stem cells, such a self-renewal capacity and the ability to differentiate into other cells. tumors exhibiting very poor infiltration of CD8+ T cells, especially in cancer cell-rich areas. T cell fate characterized by a progressive decrease of effector functions, elevated and sustained expression of immune inhibitory receptors, impaired memory and self-renewal capacity, transcriptional and epigenetic reprogramming, and altered metabolic profile. inheritable alteration in the DNA of a cell that involves the substitution of a nucleotide containing a purine for a pyrimidine or vice versa. heterogenous population of cancer cells (parenchyma), non-malignant cells (stromal cells), extracellular matrix, and signaling molecules in specific areas of tumors. number of cancer cell-specific nonsynonymous somatic mutations in a tumor, per megabase of a genetic region of interest. Such mutations drive the formation of neoantigens (i.e., antigens derived from novel mutated peptides or proteins and, therefore, are not present in the normal genome). metabolic phenotype caused by altered expression of enzymes and transporters associated with the urea cycle; limits the function of the urea cycle, promoting diversion of nitrogen toward pyrimidine synthesis, increasing mutagenesis, cell proliferation, and ICB responses.