Language
English
Publication Date
8-17-2026
Journal
Cancer Immunology Research
DOI
10.1158/2326-6066.CIR-26-0278
PMID
42607147
PMCID
PMC13584615
PubMedCentral® Posted Date
9-18-2026
PubMedCentral® Full Text Version
Author MSS
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 antitumor immunity, but the mechanisms governing these states and therapeutic targets remain unclear. Here, integrating public scRNAseq datasets with TNBC cohorts, we identify a prognostic myeloid signature defined by CXCL9hi programs, associated with improved survival and enrichment of 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 (IFN) conditioned tumor milieu that supports CXCL9⁺ monocyte-derived macrophages (Mo.Macs) in basal-like disease. Combining CTX with the next generation MERTK-selective inhibitor UNC2371 (MRX-2843) drives complete remission in both models, but durable long-term responses occurred selectively in the basal-like subtype model. Antigen-presenting CXCL9⁺ Mo.Macs expand and C1Q⁺ TAMs are reduced in responding tumors. Mechanistically, MERTK inhibition relieves MAPK/SOCS1 mediated restraint of IFN signaling driving CXCL9 induction. Functionally, tumor control requires CXCL9-CXCR3 dependent CD4⁺ T cell recruitment and correlates with the accumulation of stem-like memory CD4⁺ T cells, and germinal center-associated lymphoid organization in tumor-draining lymph nodes. PD-1 blockade further increases durability, preventing recurrence in most treated basal-like tumors. Together, these findings define an IFN licensed, MERTK regulated myeloid checkpoint that can be therapeutically targeted to convert suppressive TNBC microenvironments into durable adaptive immunity, supporting clinical translation of CTX + MRX-2843 based combinations in basal-like TNBC.
Published Open-Access
yes
Recommended Citation
Smith, Alex J; Schrank, Zachary; Guan, Nan; et al., "MERTK Inhibition Cooperates With Immunomodulatory Cyclophosphamide To Induce CXCL9⁺ Monocyte-Macrophage Programming and Durable Antitumor Immunity in Triple Negative Breast Cancer" (2026). Faculty, Staff and Students Publications. 8250.
https://digitalcommons.library.tmc.edu/baylor_docs/8250