MYC promotes the progression of prostate cancer by regulating CD47 to induce an immunosuppressive microenvironment.

MYC typically drives the growth of prostate cancer (PCa) cells, but its role in the PCa tumor immune microenvironment (TIME) remains unclear. In this study, we aimed to investigate the function and regulatory mechanisms of MYC in the TIME of PCa. Firstly, single-cell RNA sequencing (scRNA-seq) analysis demonstrated that the proportion of CD8(+) T cells in PCa samples was significantly lower than that in paracancerous samples, whereas the proportion of M2 was opposite. Additionally, the expression levels of MYC and SIRPα were upregulated in PCa cells and macrophages, showing a gradual increase with cellular differentiation. Subsequently, MYC was shown to potentially induce M2 polarization and decrease the proportion of CD8(+) T cells, an effect that may be mediated by the CD47-SIRPα interaction, as confirmed by western blotting, transwell, colony-formation, EdU, immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), and flow cytometry assays. Furthermore, polarized M2 can further facilitate the proliferation and migration of PCa cells. Finally, multiplex immunofluorescence confirmed a high infiltration level of M2 macrophages in PCa tissues, whereas CD8(+) T cell infiltration was conversely low. These findings may reveal a mechanism for immune evasion in PCa, highlighting the potential for developing MYC-targeted therapeutics to overcome resistance to immune checkpoint therapy in PCa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-026-06109-0.