VEGF/VEGFR targeting-induced vascular normalization: a key strategy to reverse cold tumor phenotype and potentiate...

The vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) pathway serves as a core driver of "cold tumor" phenotype formation in gynecologic malignancies such as ovarian cancer (OC), endometrial cancer (EC), and cervical cancer (CC), exerting dual regulatory effects on angiogenesis and immunosuppression. Vascular abnormalities mediated by this pathway, including structural disorganization, hyperpermeability, and inadequate pericyte coverage, synergize with tumor-derived high solid stress to elevate interstitial fluid pressure (IFP), collectively laying the foundation for the establishment of an immunosuppressive tumor microenvironment (TME). Meanwhile, the pathway further reinforces "cold tumor" characteristics through multiple mechanisms: impeding T cell infiltration, suppressing effector T cell function, expanding immunosuppressive cell populations such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and impairing the antigen-presenting capacity of dendritic cells (DCs). These effects result in limited efficacy of immune checkpoint inhibitor (ICIs) monotherapy. The combination strategy of VEGF/VEGFR inhibitors and ICIs, leveraging the synergistic effects of promoting vascular normalization and reversing immunosuppression, can effectively drive the conversion of "cold tumors" to "hot tumors". This review systematically summarizes the preclinical and clinical research progress of this combination regimen, focuses on analyzing the efficacy differences and subtype-specific adaptability across different cancer types, and thoroughly discusses key challenges including precise stratification based on biomarkers, deciphering drug resistance mechanisms, and safety management. This combination strategy holds significant translational potential in reversing the immunosuppressive TME of gynecologic malignancies and expanding the population benefiting from immunotherapy, thereby providing new research and clinical directions for overcoming the bottleneck of immunotherapy resistance in "cold tumors".