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.