MERTK inhibition cooperates with immunomodulatory cyclophosphamide to induce CXCL9-positive monocyte-macrophage programming and durable anti-tumor immunity in triple negative breast cancer

Triple negative breast cancer (TNBC) has high rates of recurrence despite chemotherapy and immune checkpoint blockade (ICB). Tumor associated macrophages (TAMs) can either suppress or support anti-tumor immunity, but the mechanisms governing these states and their therapeutic targeting remain unclear. Here, by integrating public single-cell datasets with TNBC patient cohorts, we identify a prognostic myeloid signature defined by CXCL9-high and C1Q-low TAM programs that is associated with improved survival and increased lymphocyte activation pathways. Using immunocompetent p53-null syngeneic TNBC models spanning basal-like (2153L) and claudin-low (T12) subtypes, we show that immunomodulatory cyclophosphamide (CTX) reprograms hematopoiesis toward the monocytic lineage and induces an interferon conditioned tumor microenvironment that supports CXCL9-positive monocyte-derived macrophages in basal-like disease. Combining CTX with the next generation MERTK-selective inhibitor ULC2371 (MRX-2843) drives complete tumor remissions in both models; however, durable long-term responses occur selectively in the basal-like subtype. Responding tumors exhibit expansion of antigen-presenting CXCL9-positive monocyte-derived macrophages and a reduction of C1q-positive phagocytic TAMs. Mechanistically, MERTK inhibition relieves MAPK and SOCS1 mediated restraint of interferon signaling, driving a positive feedback loop involving IRF7, STAT1, and IRF1 that promotes sustained CXCL9 induction. Functionally, tumor control requires CXCL9-CXCR3 dependent CD4 T cell recruitment, accumulation of stem-like memory CD4 T cells, and germinal center-like immune organization in tumor draining lymph nodes. PD-1 blockade further enhances response durability, preventing recurrence in most treated basal-like tumors.Together, these findings define an interferon-licensed, MERTK-regulated myeloid checkpoint that can be therapeutically targeted to convert immunosuppressive TNBC microenvironments into durable adaptive immunity, supporting clinical translation of CTX and MRX-2843 based combination therapies in basal-like TNBC.