MLKL PARylation in the endothelial niche triggers angiocrine necroptosis to evade cancer immunosurveillance and chemotherapy

Abstract

Chemoresistance is the leading cause of cancer-related death. How chemotherapy subjugates the cellular crosstalk in the tumour microenvironment to cause chemoresistance remains to be defined. Here we find chemotherapy enables immunosuppressive SDF1⁺ endothelial niche to evade immunosurveillance in ovarian and breast cancers. We integrated human patient data and mouse models to show that chemotherapy selectively activates PARP1-SDF1 axis in tumour endothelial cells (ECs). This angiocrine SDF1 interferes with antitumour interplay between CXCL10⁺ macrophages and CXCR3⁺CD8⁺ T cells and promotes tumour progression in ovarian and breast cancers. Proteome-based screening revealed that endothelial PARP1 PARylates MLKL, a key necroptosis effector to upregulate angiocrine SDF1 in ECs. In sum, we identify PARylation-dependent necroptosis in tumour ECs as an important step in subverting the tumour microenvironment to evade immunosurveillance.