Myeloid cells render TNBC resistance to anti-PD1 therapy via IFNγR1

The pro-tumoral effects of interferon γ receptor 1 (IFNγR1) has been observed in subsets of patients receiving anti-programmed cell death protein 1 (anti-PD1) therapy, but the underlying mechanism remain unclear. Clinical database analysis indicated that IFNGR1 transcription levels were negatively associated with survival in triple-negative breast cancer (TNBC) patients. In the murine EO771 TNBC model, host Ifngr1 deficiency significantly enhanced the efficacy of anti-PD1 therapy by promoting CD8⁺ T cell activation, reducing intratumoral monocytes, and inducing the polarization of macrophage toward an M1-like phenotype. scRNA-seq analysis further revealed that host Ifngr1 deficiency strengthened MHC-I-mediated interactions between myeloid cells and CD8⁺ T cells, and enhanced antigen presentation and antitumor immunity. By using LysMcre; Ifngr1f/f conditional knockout mice, we demonstrated that myeloid-derived IFNγR1 corresponded to anti-PD1 resistance in murine TNBC tumors. In line with the preclinical results, TCGA analysis confirmed that low IFNGR1 expression was associated with improved survival in patients with high monocyte proportions. Collectively, these findings suggest that IFNγR1 on myeloid cells facilitates the resistance of TNBC tumors to PD1 blockade therapy, highlighting myeloid-derived IFNγR1 as a potential therapeutic target to improve anti-PD1 efficacy in TNBC.