Efferocytosis induces proangiogenic function and chromatin remodeling in tumor-associated macrophages

Macrophages remove apoptotic cells by efferocytosis during immune surveillance and in the tumor microenvironment (TME). However, the gradual molecular and epigenetic consequences of efferocytosis in single macrophages remain unclear. Here, we introduce Effero-seq, an approach that captures single-cell transcriptomic changes coupled with lysosomal acidification tracked by a pH-sensitive dye (pHrodo), thus enabling the dissection of molecular dynamics over time after engulfment. Using labeled apoptotic cells as cargo, we defined the effero-score, a gene program gradually up-regulated in correlation with pHrodo intensity. In a murine melanoma model, efferocytosis induced a proangiogenic function in macrophages with spatial proximity to vascular niches. Moreover, efferocytosis remodeled chromatin accessibility, leading to an attenuated macrophage response to interferon-γ. In human uveal melanoma, expression of the effero-score was correlated with poor survival. Therefore, Effero-seq sheds light on the molecular reprogramming induced by efferocytosis in the TME, opening previously unknown avenues for understanding macrophage function and developing targeted treatments.