Tumors suppress a mitochondrial chaperone activity in macrophages to facilitate immune evasion 2455

Abstract Description Unlike the dysfunctional mitochondria of tumor-infiltrating T cells, tumor-associated macrophages (TAMs) maintain their functional mitochondria in the nutrient-deprived tumor microenvironment (TME), promoting an immunosuppressive phenotype. However, the mechanisms underlying this remain unclear. Here, we identify that TNF-receptor associated protein-1 (TRAP1), a mitochondrial chaperone, serves as an endogenous metabolic checkpoint that regulates mitochondrial respiration and drives immunosuppressive function in TAMs. In the TME, TRAP1 expression in TAMs is suppressed via the TIM4-AMPK pathway. Using TRAP1-deficient mice, we observed that TRAP1 loss amplifies immunoinhibitory function in macrophages while reducing proinflammatory activity. Mechanistically, TRAP1 absence enhanced activity of mitochondrial electron transport chain complexes and increased the α-ketoglutarate (α-KG) to succinate ratio. The increase in α-KG facilitates JMJD3-mediated histone demethylation, altering genes expression associated with immunosuppressive activation in macrophages and thereby facilitating tumor immune escape. Notably, boosting TRAP1 expression in TAMs disrupts the immunosuppressive TME, bolstering anti-tumor immunity. These findings underscore TRAP1’s pivotal role in TAM metabolic rewiring and immune modulation, highlighting its potential as a therapeutic target in cancer immunotherapy. Funding Sources Supported by American Cancer Society Research Scholar Grant (RSG-22-135-01-IBCD), Melanoma Research Foundation Career Development Award, Andrew McDonough B+ Foundation Grant Award, Cancer Research Institute CLIP Investigator Award, Case Comprehensive Cancer Center American Cancer Society Pilot Grants (IRG-91-022-19, IRG-16-186-21). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)