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

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.