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 on the single macrophage are not thoroughly elucidated. Here we introduce Effero-seq, an approach that captures single-cell transcriptomic changes coupled with lysosomal acidification tracked by pHrodo, thus enabling the dissection of molecular dynamics over time following engulfment. Using apoptotic pHrodo-labeled cells as cargo, we defined the effero-score, a gene program gradually upregulated correlatively with pHrodo intensity. In a murine melanoma model, we found that efferocytosis induces a pro-angiogenic function in macrophages with spatial proximity to vascular niches. Moreover, efferocytosis reprograms chromatin accessibility, leading to attenuated macrophage response to IFNγ. In human uveal melanoma, expression of the effero-score is correlated with poor survival. Effero-seq sheds light on the molecular reprogramming induced by efferocytosis in the TME, opening new avenues for understanding macrophage function and developing targeted treatments.