Dual Functions of B7-H3-MAPK Signaling Orchestrate Tumor Immunosuppression via Regulating the Plasticity of Myeloid-derived Suppressor Cells and Fibroblasts.

B7-H3/CD276 is an emerging immunotherapy target in cancers. However, limited knowledge of B7-H3 signaling and its role in modulating the tumor microenvironment hinders the clinical application of B7-H3-targeting therapy. Here, we report that B7-H3 plays dual roles in regulating myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs), thereby promoting tumor progression and therapy resistance, respectively. We comprehensively characterized a non-canonical function of B7-H3 that triggers MAPK signaling in monocytic MDSCs and induces cellular senescence. The senescent monocytic M-MDSCs secreted chemokines to recruit immunosuppressive granulocytic MDSCs. Genetic deletion or pharmacological inhibition of B7-H3/Cd276 reduced Gr-MDSCs and delayed tumor progression. Nevertheless, the secretory factor SPINK1 derived from MDSCs compensatorily activates EGFR/MEK/ERK signaling in CAFs and promotes their extracellular matrix remodeling features, dampening B7-H3-targeting immunotherapy. Combining the B7-H3 monoclonal antibody with the FDA-approved MEK inhibitor trametinib showed durable anti-tumor effects in preclinical models of castration-resistant prostate cancer by fully attenuating immunosuppressive mechanisms.