ANXA2‐mediated Phagocytosis Generates AR + Macrophages to Confer Enzalutamide Resistance in Prostate Cancer

ABSTRACT Resistance to second‐generation antiandrogens like enzalutamide (ENZ) in castration‐resistant prostate cancer (CRPC) is a major clinical challenge, yet the role in the tumor microenvironment remains poorly understood. This study identifies a unique AR‐positive tumor‐associated macrophages (AR + TAMs) subpopulation, enriched in ENZ‐resistant patients and correlated with poor prognosis, which acquires functional AR protein not through endogenous expression but via ANXA2‐dependent phagocytosis of tumor cells. The internalized AR protein translocates to the macrophage nucleus, directly binds the IL‐6 promoter to enhance its transcription and secretion. Macrophage‐derived IL‐6 subsequently activates the JAK2/STAT3 pathway in cancer cells, suppressing ENZ‐induced apoptosis and conferring therapeutic resistance. Genetic or pharmacological blockade of IL‐6 signaling restored ENZ sensitivity in vitro and in vivo, and combining an anti‐IL‐6 antibody with ENZ synergistically overcomes resistance in patient‐derived xenograft and orthotopic models. These findings reveal a novel phagocytosis‐mediated, paracrine mechanism of ENZ resistance orchestrated by AR + TAMs, challenging the tumor‐centric view of therapy failure and providing a strong rationale for co‐targeting the IL‐6 pathway to improve outcomes of AR‐directed therapy in CRPC.