Distinct TAM subset with cross-dressing capability determines the bifurcation of tumor immunity

Summary: Tumor-associated macrophage (TAM) heterogeneity significantly influences the tumor microenvironment, positioning TAM inhibition as a promising anticancer strategy. Although several TAM subsets have been described, their functional roles remain unclear. In this study, we identified a distinct subset of CD9hiCD63hiCD206+Class IIlo hypoxic TAMs, located near tumors. These TAMs engage in trogocytosis, acquiring tumor membrane fragments, and cross-dress major histocompatibility complex (MHC)/tumor antigen epitopes. These processes facilitate their recognition by cytotoxic T lymphocytes, enhancing antitumor immune responses. We further found CH25H as a key regulator of TAM cross-dressing, with its inhibition associated with the activity of HIF1-α and VHL. These findings highlight the potential of modulating TAMs as an innovative immunotherapy strategy.