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.