Abstract Prostate cancer is inherently resistant to immune checkpoint inhibitors (ICIs). While the role of myeloid cells within tumors contributing to immune suppression has long been appreciated, therapeutic approaches targeting myeloid cells have been unsuccessful thus far. By using multi-omic single-cell profiling of prostate cancer patient biopsies, we find that distinct populations of tumor-associated myeloid cells mediate immunosuppression within different disease contexts. Tumor-associated macrophages expressing elevated SPP1 transcripts (SPP1 hi-TAMs) becomes enriched with prostate cancer disease progression to mCRPC. Through in vitro and in vivo studies, we found that Spp1 hi-TAMs are potently immunosuppressive at least in part through the adenosine pathway. Pharmacologic inhibition of adenosine receptors, A2AR, reverses Spp1 hi-TAM-mediated immune suppression on CD8+ T cells in vitro and enhances CRPC responsiveness to PD-1 blockade in vivo. Moreover, we find that inhibiting A2AR results in a significant decrease in SPP1 hi-TAM abundance in CRPC, indicating that this pathway is involved in both their induction and downstream immunosuppression. While these myeloid cells are found in primary prostate cancer and metastasis to soft tissue, we have found that bone metastases possess distinct myeloid populations. In this site, we identified a mature population of neutrophils that mediate immunosuppression through IL-1beta. IL-1R blockade restores CD8+ T cell function and enhances ICI responses. These results demonstrate has different disease contexts can lead to different mechanism of myeloid-mediated immunosuppression. Citation Format: Aram Lyu, Zenghua Fan, Lawrence Fong. Myeloid-mediated mechanisms of resistance to immunotherapy in prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr IA002.
Lyu et al. (2026) studied this question.