A Pan-cancer single-cell analysis reveals the effect of PD-1 blockades on tumor angiogenesis by inhibiting the endothelial CXCL12-CXCR4 axis

Immune checkpoint inhibitors (ICIs), particularly programmed cell death protein 1 (PD-1) blockades, have redefined oncology in the last decade. Previous studies on PD-1 blockades mostly concentrate on their interactions with immune cells. This study aims to investigate how PD-1 blockades affect endothelial cell (EC) heterogeneity in the tumor microenvironment (TME) and to explore potential targets for enhancing the anti-tumor effects of PD-1 blockades. Here, we established a pan-cancer EC atlas from the public database and revealed that PD-1 blockades repress the angiogenic population in ECs and inhibit the CXCL12-CXCR4 signaling derived from ECs. Using a murine tumor model built with Lewis Lung Carcinoma cell line, we further validated our findings that a PD-1 blockade, as well as a CXCR4 antagonist AMD3100, inhibited EC population in tumors and their CXCL12 expression. In addition, the combo therapy of the PD-1 blockade and AMD3100 showed significantly superior anti-tumor effects to monotherapy. Moreover, we predicted MYC to be the potential regulator through which PD-1 blockades affect ECs. Together, our results suggest that PD-1 blockades play an anti-angiogenic effect besides boosting T cell immunity, and the CXCL12/CXCR4 pathway is a potential target for enhancing the effectiveness of PD-1 blockades.