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Life sciences · Journal article
Cell Death Discovery · October 6, 2026
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Abstract Resistance to anti-angiogenic therapy remains a major obstacle in non–small cell lung cancer (NSCLC). Although bevacizumab effectively neutralizes VEGFA and suppresses neovascularization, its clinical benefit is often transient. Here, we demonstrate that VEGFA inhibition paradoxically intensifies intratumoral hypoxia, leading to stabilization of HIF1A and activation of a compensatory pro-malignant program. Increased HIF1A not only enhances tumor cell migration, epithelial–mesenchymal transition, and chemoresistance, but also upregulates CD105 (Endoglin), a hypoxia-responsive pro-angiogenic mediator that attenuates the anti-vascular effects of bevacizumab. Thus, anti-VEGFA therapy initiates a hypoxia-driven HIF1A–CD105 axis that sustains tumor aggressiveness and vascular adaptation despite VEGFA blockade. We identify the pre–miR-16-1 duplex as a physiological dual-regulatory system capable of simultaneously targeting this adaptive circuit. The guide strand miR-16-5p directly represses VEGFA, recapitulating the anti-angiogenic action of bevacizumab. In contrast, the passenger strand miR-16-1-3p suppresses HIF1A expression, thereby preventing hypoxia-induced malignant phenotypes and limiting CD105 upregulation. Functional analyses revealed that VEGFA inhibition was accompanied by HIF1A upregulation, while elevated HIF1A promoted cell migration, mesenchymal-like changes, and cisplatin resistance. Co-expression of miR-16-1-3p suppressed HIF1A and attenuated these adverse phenotypes. In a chick chorioallantoic membrane xenograft model, dual regulation of VEGFA and HIF1A markedly reduced vascular density, tumor growth, and metastatic dissemination compared with single anti-angiogenic intervention. Collectively, our findings uncover a hypoxia-mediated resistance mechanism driven by the HIF1A–CD105 axis following VEGFA inhibition and establish the cooperative function of the miR-16 duplex as a strategy to concurrently suppress angiogenesis and its adaptive hypoxic feedback. Concurrent targeting of VEGFA and HIF1A may therefore provide a strategy to enhance the antitumor efficacy of anti-angiogenic therapy in NSCLC.