DataVXAdvanced SciencePaper
journal article·2026-07Open access

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

Yong Luo, Tianlong Luo, Lingfeng Li, Qi Sun, Dongquan Li, Shanhe Huang, Zonglin Li, Weilong Lin, Yuan Ou, Tao Du, Shengmeng Peng, Kewei Xu, Bisheng Cheng, Hai Huang

Advanced Science· Volume 13· Issue 38
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: Prostate Cancer Treatment and Research · Immune cells in cancer · Phagocytosis and Immune Regulation

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Urology Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou Guangdong China

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong China

Vancouver Prostate Centre Department of Urologic Sciences University of British Columbia Vancouver British Columbia Canada

Beijing Hospital National Center of Gerontology Institute of Geriatric Medicine Chinese Academy of Medical Sciences & Peking Union Medical College Beijing China

Department of Urology Nanfang Hospital Southern Medical University Guangzhou Guangdong China

Department of Obstetrics and Gynecology Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong China

Guangdong Provincial Clinical Research Center for Urological Diseases Sun Yat‐Sen Memorial Hospital Sun Yat‐Sen University Guangzhou Guangdong China

Southern Medical University Guangzhou Guangdong China

Department of Clinical Oncology Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China

Department of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen China

Department of Surgery Division of Urology Beth Israel Deaconess Medical Center Harvard Medical School Boston Massachusetts USA

Department of Urology The Sixth Affiliated Hospital of Guangzhou Medical University Qingyuan People's Hospital Qingyuan Guangdong China

Funding

National Natural Science Foundation of China · Beijing Xisike Clinical Oncology Research Foundation · China Postdoctoral Science Foundation

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