Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer.

This study explores the role of efferocytosis in esophageal squamous cell carcinoma (ESCC) using single-cell RNA sequencing and in vitro/in vivo assays. Analyzing 27 samples from 9 patients with ESCC, we identify diverse cell types and significant heterogeneity in the tumor microenvironment, with a focus on efferocytosis. Our findings highlight that macrophages engulf apoptotic tumor cells, thereby impairing immune responses and promoting tumor progression. Notably, TP63 and RAC2 emerge as key regulators of this process, influencing efferocytosis and immune modulation. Functional assays demonstrate that disrupting these pathways alters macrophage efferocytosis and impacts tumor growth in vivo. These results suggest that targeting efferocytosis pathways offers potential therapeutic strategies for ESCC, enhancing antitumor immunity and improving patient outcomes. The study underscores the complex interactions between tumor cells and the immune system, with efferocytosis representing a promising therapeutic target.