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ANXA2-mediated Phagocytosis Generates AR+ Macrophages to Confer Enzalutamide Resistance in Prostate Cancer
Yong Luo1,2, Tianlong Luo1,3, Lingfeng Li4
1Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
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.
Insights
Tumor-associated macrophages acquire androgen receptor (AR) protein, driving resistance to enzalutamide (ENZ) in prostate cancer. Blocking IL-6 signaling with ENZ overcomes this resistance, improving treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Enzalutamide (ENZ) resistance is a major challenge in castration-resistant prostate cancer (CRPC).
- The tumor microenvironment's role in ENZ resistance is not fully understood.
Purpose of the Study:
- To investigate the mechanism of ENZ resistance involving tumor-associated macrophages (TAMs).
- To identify novel therapeutic strategies targeting the tumor microenvironment to overcome ENZ resistance.
Main Methods:
- Identification and characterization of AR-positive TAMs (AR+ TAMs) in CRPC patients.
- Investigation of AR protein acquisition by TAMs via phagocytosis.
- Analysis of IL-6 secretion by AR+ TAMs and its effect on cancer cells.
- Evaluation of IL-6 blockade and combination therapy (anti-IL-6 antibody + ENZ) in vitro and in vivo models.
Main Results:
- A unique AR+ TAM subpopulation was identified, associated with ENZ resistance and poor prognosis.
- TAMs acquired functional AR protein through phagocytosis of tumor cells, not endogenous expression.
- Macrophage-derived IL-6 activated JAK2/STAT3 signaling in cancer cells, promoting ENZ resistance.
- Blocking IL-6 signaling restored ENZ sensitivity, and combination therapy synergistically overcame resistance.
Conclusions:
- AR+ TAMs mediate ENZ resistance via a novel phagocytosis-dependent IL-6 paracrine signaling loop.
- This study challenges the tumor-centric view of therapy failure and highlights the immune microenvironment's role.
- Co-targeting the IL-6 pathway with enzalutamide offers a promising strategy to improve AR-directed therapy outcomes in CRPC.
