DLL1-responsive PD-L1⁺ tumor-associated macrophages promote endocrine resistance in breast cancer

Estrogen receptor–positive (ER⁺) luminal breast cancer comprises 75% of patients with breast cancer and presents notable treatment challenges because of endocrine resistance. The effectiveness of immunotherapy in endocrine therapy–resistant luminal breast cancer remains unclear. This limitation is due in part to a lack of immunocompetent preclinical models investigating the comprehensive involvement of immune cells in the tumor microenvironment (TME) in the context of endocrine resistance. In this study, we identified a subtype of immunosuppressive (M2-like) programmed death ligand 1–positive (PD-L1⁺) tumor-associated macrophages (TAMs) critically fostering resistance to tamoxifen (TMX) and fulvestrant (FV) through maintaining cancer stem cell (CSC) activity in new mouse models. These TAMs are recruited by Delta-like ligand 1 (DLL1), a Notch signaling ligand expressed in luminal tumor cells, through the CCR3/CCL7 axis. Combination therapy with anti-DLL1 and anti–PD-L1 antibodies with TMX reduced tumor growth and associated CSCs and reprogrammed the immunosuppressive TME in both preclinical mouse models and patient-derived explants, thus laying the foundation for a future combined immune-endocrine therapy in these patients.