Prostate cancer cell lines and patient samples were analyzed using immunohistochemistry, flow cytometry, and mass spectrometry. Tumor-bearing mice were injected with human PBMCs, and the IL-8/CXCR2 pathway was targeted for intervention. The resulting changes in the tumor immune microenvironment were then assessed.

The IL-8/CXCR2 pathway was found to be overexpressed in advanced prostate cancer, promoting the accumulation of free fatty acids (FFAs) and very-long-chain polyunsaturated fatty acids (VLC-PUFAs) and triggering ferroptosis in tumor-infiltrating CD8+ T cells. Regulatory T cell (Treg) infiltration also increased under these conditions. The underlying mechanism involves IL-8/CXCR2-mediated upregulation of the AKT- mTOR-FAS pathway; and activation of the mTOR-MYC-ELOVL5 axis via Rictor acetylation. Inhibition of the IL-8/CXCR2 pathway restored CD8+ T cell function and reduced immune evasion.