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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE318315 | GEO | 2026/03/11

REPOSITORIES: GEO