Macrophage sensitivity to reprogramming by bexmarilimab is shaped by the tumor microenvironment [scRNA-Seq]

Tumor-associated macrophages (TAMs) adapt to the tumor microenvironment (TME), either aiding cancer eradication or promoting tumor growth and immune evasion. To manipulate TAMs therapeutically, a deep understanding of their interaction with the TME is essential. This study exploits a breast cancer patient-derived explant culture (PDEC) model to predict TMEs responsive to bexmarilimab, a macrophage reprogramming therapy showing clinical benefit in various solid tumors. The PDEC model captured key aspects of bexmarilimab's action, validated a gene signature for predicting treatment sensitivity, and characterized responses in both tumor and adjacent cancer-free tissue. We identified three distinct treatment responses shaped by the local TME and macrophage phenotype, origin and localization. The inflammatory state of the TME was detected as the primary factor defining response to bexmarilimab. These findings emphasize the need for patient selection to maximize bexmarilimab's efficacy, particularly in immunologically cold tumors lacking late-stage activated TAMs and reveal the complexity of TAM targeting in cancer.