B7-H3-induced Myeloid–Stromal Circuit Enables Combinatorial Immunotherapy in Advanced Prostate Cancer

Abstract

Advanced prostate cancer remains largely refractory to immune-checkpoint blockade, highlighting the need to understand the cellular networks that sustain immune exclusion. In a recent study, Shi and colleagues identify tumor-cell B7-H3 as a key organizer of a myeloid–stromal circuit in prostate cancer. B7-H3 activates MEK–ERK signaling in monocytic myeloid-derived suppressor cells (M-MDSCs), inducing senescence and a CXCL2/3-rich secretory phenotype that recruits immunosuppressive granulocytic MDSCs (Gr-MDSCs) through CXCR2. However, genetic deletion or therapeutic blockade of B7-H3 produces a compensatory response: proliferating, non-senescent M-MDSCs accumulate and secrete SPINK1, which activates EGFR–MEK–ERK signaling in cancer-associated fibroblasts (CAFs), promotes extracellular-matrix remodeling and collagen deposition, and restricts T-cell access. Thus, B7-H3 activity and its inhibition engage complementary mechanisms of immune suppression, helping explain the limited efficacy of B7-H3 monotherapy. Combining a B7-H3 monoclonal antibody with the MEK inhibitor trametinib disrupts this adaptive immunosuppressive network, producing more durable tumor control in castration-resistant prostate cancer. These findings broaden B7-H3 from a tumor-associated surface antigen to a hub of cancer–myeloid–fibroblast communication and provide a mechanistic rationale for combined B7-H3 and MAPK pathway inhibition. More broadly, they show that effective immunotherapy may require targeting both the initiating checkpoint and the compensatory mechanisms to achieve durable therapeutic effects.