Host-derived interleukin-1α drives tumor immunosuppression by reprogramming tumor-associated myeloid cells.

Myeloid cells are highly heterogeneous and play key roles in establishing an immunosuppressive tumor microenvironment (TME), but the mechanisms controlling their differentiation remain unclear. Using orthotopic murine breast cancer models, we investigated how interleukin-1α (IL-1α) influences this process. Deletion of host Il1α resulted in rejection of transplanted tumors. Single-cell RNA sequencing identified CX3CR1⁺ macrophages as the main source of IL-1α in the TME. Il1α deficiency disrupted monocyte-macrophage differentiation, reducing CX3CR1⁺ macrophages and increasing iNOS⁺ macrophages. Myeloid cells from Il1α(⁻/⁻) hosts induced lower PD-1 and CTLA-4 expression in co-cultured CD8⁺ T cells than those from wild-type hosts. CellChat analysis showed that IL-1α loss rewired communication between macrophages and other immune cells, particularly affecting M-CSF, TGFβ, and PGE2 signaling. In vitro, the proinflammatory phenotype induced by Il1α deficiency in bone-derived macrophages was reversed by PGE2, indicating a key regulatory axis. Macrophages from Il1α(⁻/⁻) tumors exhibited activated immune gene signatures similar to human macrophages. These findings reveal that IL-1α drives an immunosuppressive TME partly through PGE2 signaling, highlighting IL-1α as a potential therapeutic target in breast cancer.