Tumor‐Derived Exosomes Deliver Membrane‐Bound Fgl2 to Activate FcγRIIB‐Mediated Immunosuppression in Myeloid‐Derived Suppressor Cells

ABSTRACT Myeloid‐derived suppressor cells (MDSCs) play a pivotal role in establishing an immunosuppressive tumor microenvironment (TME), yet the mechanisms underlying their functional activation remain incompletely defined. Here, we identify the Fgl2‐FcγRIIB signaling axis as a critical mediator of MDSC‐driven immune evasion across solid tumors. Analysis of clinical specimens revealed that Fgl2 expression is significantly elevated in tumor tissues and inversely correlates with CD8 + T cell infiltration, while positively associating with the accumulation of FcγRIIB + MDSCs and poor patient prognosis. We demonstrate that tumor‐derived exosomes (TEX) function as efficient carriers that deliver membrane‐bound Fgl2 (mFgl2) to MDSCs. These exosomes are internalized by MDSCs through FcγRIIB‐mediated endocytosis, leading to an enhanced immunosuppressive function characterized by upregulated arginase‐1 (Arg‐1) and inducible nitric oxide synthase (iNOS) expression and an increased capacity to suppress CD8 + T cell proliferation. Genetic ablation of FcγRIIB or antibody‐mediated neutralization of Fgl2 abolished this exosome‐mediated immunosuppressive programming, restoring T cell activity and impairing tumor growth in vivo. Importantly, a therapeutic strategy combining an exosome secretion inhibitor, in combination with PD‐L1 blockade and MDSCs depletion, synergistically achieved potent antitumor effects. Our findings unveil a novel exosome‐dependent mechanism through which tumors systemically educate MDSCs, establishing the Fgl2‐FcγRIIB axis as a promising broad‐spectrum target for cancer immunotherapy.