Drug Resistance to Anti-Angiogenic Therapy: Mechanisms, Clinical Implications, and Translational Strategies in Hepatocellular and Renal Cell Carcinoma.

Angiogenesis remains a fundamental hallmark of solid tumor growth and metastatic progression, and blocking the vascular endothelial growth factor (VEGF) pathway has changed how systemic therapy works for hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). However, the clinical benefits of anti-angiogenic therapy are frequently transient. Resistance arises from synchronized adaptive mechanisms that include redundant pro-angiogenic signaling, hypoxia-induced transcriptional reprogramming, metabolic reconfiguration, immune microenvironment alteration, and structural vascular evasion. Although the combination of VEGF blockade with immune checkpoint inhibitors (ICIs) has enhanced survival outcomes in pivotal trials such as IMbrave150 and CheckMate 9ER, sustained responses remain infrequent [1,2]. This review combines mechanistic and clinical evidence to create a comprehensive framework for anti-angiogenic resistance. We analyze ligand redundancy (FGF, PDGF, Ang-2), hypoxia-inducible factor (HIF)-mediated metabolic adaptation focused on glycolysis and lactate export, endothelial glycolytic regulation through PFKFB3, myeloid-driven immunosuppression, and structural resistance mechanisms such as vessel co-option and vasculogenic mimicry. We integrate these biological domains with phase III clinical trial data from HCC and RCC and suggest a translational roadmap that prioritizes orthogonal metabolic targeting, microenvironmental reprogramming, structural interception, and biomarker-guided adaptive scheduling at the top of the list during the vascular normalization window. Reconceptualizing resistance as a systems-level adaptive network establishes a basis for more resilient and region-specific therapeutic approaches.