Pancancer pro-angiogenic atlas unravels tumor-educated pericyte-augmented anti-angiogenic resistance

Targeting angiogenesis represents a cornerstone in the development of antitumoral therapy, yet the suboptimal responses and inevitable resistance significantly limit its clinical efficacy. To better understand the mechanisms underlying anti-angiogenic resistance, this study systematically characterized the pancancer angiogenic landscape based on 1.24 million individual cells across 13 cancer types. Our analyses revealed that pericytes (PCs) and PC-derived non-classical angiogenic factors PGF/ANGPT2 correlate with angiogenesis more prominently than the classical VEGFA-centric model. Tumor-educated PCs, namely MCAM + immature PCs (imPCs), were spatio-transcriptionally identified as the primary source of PGF/ANGPT2, driving alternative angiogenesis and serving as a major contributor to ɑVEGFR resistance. MCAM + imPCs were phenotypically shaped under the dysregulated Notch signaling and hypoxia stress. To address the limitations associated with single-targeted endothelial cells (ECs) inhibition via ɑVEGFR, we adopted MCAM-directed antibody-drug conjugate (MCAM ADC) to specifically eliminate pro-angiogenic PCs, whose combination with ɑVEGFR showed enhanced anti-angiogenic effects. This dual-targeting approach demonstrated superior tumor control, offering MCAM ADC as a promising translational solution to circumvent anti-angiogenic resistance. Overall, our findings redefine the mechanisms of angiogenic resistance and suggest a dual EC/PC inhibition strategy for more effective anticancer therapy.