Anti-CSF-1R therapy with combined immuno-chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched triple negative breast cancers
- Diego A. Pedroza
- Xueying Yuan
- Fengshuo Liu
- Hilda L. Chan
- Christina Zhang
- William Bowie
- Alex J. Smith
- Sebastian J. Calderon
- Nadia Lieu
- Weiguo Wu
- Paul Porter
- Poonam Sarkar
- Na Zhao
- Constanze V. Oehler
- Ondrej Peller
- M. Waleed Gaber
- Qian Zhu
- Charles M. Perou
- Xiang H.-F. Zhang
- Jeffrey M. Rosen
2026-01-04
Women diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-5 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.