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Neuroendocrine prostate cancer (NEPC) is characterized by strong immune evasion and profound metabolic reprogramming. A high regulatory T cell (Treg)/CD8⁺ T cell ratio and an increased proportion of M2/M1 tumor-associated macrophages (TAMs) in the NEPC tumor microenvironment (TME) are associated with poorer progression-free survival, a phenomenon linked to lipid accumulation within the TME. Understanding the regulatory mechanisms governing both the metabolic and immune landscapes of NEPC is critical.

To investigate these mechanisms, prostate cancer cell lines and patient samples were analyzed using immunohistochemistry, flow cytometry, PCR, western blotting, and mass spectrometry. The interleukin (IL)-8/CXCR2 signaling pathway was targeted for intervention in two tumor-bearing mouse models.

Data revealed that IL-8/CXCR2 signaling drives the accumulation of free fatty acids and very-long-chain polyunsaturated fatty acids, leading to ferroptosis in tumor-infiltrating CD8⁺ T cells. This, in turn, promotes Treg cell infiltration and an M2 macrophage-dominant immune landscape. Mechanistically, IL-8/CXCR2 signaling upregulates the AKT-mTOR-FAS pathway while activating the mTOR-MYC-ELOVL5 axis via Rictor acetylation. In preclinical studies using NSG and B57BL/6 mouse models, CXCR2 inhibition restored CD8⁺ T cell antitumor activity and enhanced TAM phagocytosis, significantly reducing tumor growth.

These findings highlight CXCR2 as a promising immunotherapeutic target for NEPC and underscore its relevance in translational medicine.