FCGR2B drives immunosuppressive M2 polarization of tumor-associated macrophages via metabolic reprogramming of fatty acid oxidation.

Abstract

FCGR2B, the only inhibitory receptor in the Fcγ receptor family, plays a crucial role in both innate and adaptive immunity. In this study, we observed high FCGR2B expression in tumor-associated macrophages (TAMs) induced by B16 melanoma cells. Knockdown of Fcgr2b in these TAMs suppressed their M2 polarization, as evidenced by decreased expression of immunosuppressive factors, including Arg-1, IL-10, and Fizz1. Furthermore,Fcgr2b knockdown enhanced the phagocytic and antigen-presenting capacities of TAMs, promoted ROS production, and improved their ability to kill melanoma cells in vitro. Transcriptomic analysis revealed thatFcgr2b knockdown predominantly affected key metabolic and signaling pathways, including the JAK-STAT and PPAR-γ pathways. Using classic pharmacological inhibitors (2-DG and C75), we confirmed that FCGR2B interference remodels glycolipid metabolism in TAMs, which is characterized primarily by attenuated fatty acid metabolism, accompanied by increased glycolysis and intracellular free fatty acid accumulation. Moreover, FCGR2B interference downregulated the fatty acid oxidation key enzyme CPT1a by inhibiting the JAK/STAT6/PPAR-γ signaling axis, thereby reducing fatty acid oxidation. Concomitantly, it alleviated endoplasmic reticulum stress via the IRE1/XBP1 pathway, ultimately attenuating the tumor-promoting phenotype of TAMs. Our findings delineate a mechanism by which FCGR2B integrates metabolic and signaling pathways to regulate TAM function, providing a mechanistic basis for targeting FCGR2B in cancer immunotherapy.