CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: These findings highlight CXCR2 as a promising immunotherapeutic target for NEPC and underscore its relevance in translational medicine.