Targeting CXCR2 in prostate cancer cells can block CD47-SIRPα interaction and reverse M2 macrophage polarization in the TME.

Neuroendocrine prostate cancer (NEPC) exhibits strong immune evasion and plays a critical role in regulating metabolic reprogramming within prostate cancer. High infiltration of CD36 + M2 tumour-associated macrophages (TAMs) and elevated CD47 expression in NEPC cells are often associated with poor progression-free survival in cancer patients. Understanding the mechanisms that regulate CD36 + M2 TAM infiltration and high CD47 expression in tumour cells within the prostate cancer tumour microenvironment (TME) is essential. Using cell models and two animal models, we discovered that the IL-8/CXCR2 pathway increases acetyl-CoA levels through metabolic reprogramming, which subsequently increases CD47 expression via acetylation. Moreover, this pathway modulates the membrane localization of CD47 by stimulating tumour cells to secrete palmitic acid and utilize palmitoylation mechanisms, thereby protecting tumour cells from macrophage-mediated phagocytosis. The IL-8/CXCR2 pathway also reshapes the metabolic microenvironment of the TME, increasing the infiltration of ω-3/6 polyunsaturated fatty acids (PUFAs) in the TME, which promotes the recruitment of CD36 + M2 TAMs. Preclinical studies in both NSG and C57BL/6 animal models demonstrated that targeting CXCR2 restored TAM phagocytic activity and significantly reduced tumour growth. These findings suggest that CXCR2-targeted immunotherapy holds promising therapeutic potential for prostate cancer and underscores its importance in translational medicine.