AR(+)TREM2(+) macrophage induced pathogenic immunosuppression promotes prostate cancer progression.

The androgen receptor (AR) usually drives prostate cancer cell growth, yet its role in immune cells such as tumour-associated macrophages (TAMs), remains unclear. We find that macrophages co-expressing AR and triggering receptor expressed on myeloid cells-2 (TREM2) exhibiting potent immunosuppressive and tumour-promoting effects. Genetic ablation of TREM2 combined with pharmacological blockade of AR, significantly reduces tumour progression in prostate cancer mouse models. Mechanistically, apolipoprotein E (APOE) in tumour microenvironment (TME) binds to TREM2 on macrophages and promotes AR expression. AR further upregulates transcription expression of Il10, Tgfb1, Il23a, and Ccl2 in macrophages. AR, TREM2, and APOE expression increases in prostate cancer patients and correlates with poor prognosis. In conclusion, these findings indicate an alternative mechanism of tumour immune evasion, supporting the development of immunomodulatory agents targeting AR and TREM2 in TAMs to delay or reverse endocrine therapy resistance or immune checkpoint therapy resistance in prostate cancer.