Mechanistic synergies and optimal sequencing of anti‑VEGF plus immune checkpoint inhibition in gastrointestinal cancers

Gastrointestinal (GI) malignancies remain leading causes of cancer-related mortality despite advances in therapeutic strategies. This review was undertaken to provide a comprehensive synthesis of the mechanistic rationale, preclinical evidence, and clinical data supporting the combination of anti-vascular endothelial growth factor (anti-VEGF) agents with immune checkpoint inhibitors (ICIs) in GI cancers, with particular emphasis on optimal sequencing strategies and unresolved challenges. We performed a narrative review of the literature, integrating preclinical studies on tumor microenvironment (TME) dynamics with key phase II/III clinical trials across hepatocellular carcinoma (HCC), colorectal cancer (CRC), gastric/gastroesophageal junction cancers, pancreatic ductal adenocarcinoma, and other GI malignancies. The core rationale for this combination stems from complementary mechanisms: anti-VEGF therapy induces vascular normalization, enhances immune cell infiltration, and reduces immunosuppression within the TME, thereby converting immunologically "cold" tumors into "hot" tumors that are more responsive to checkpoint blockade. Clinically, the strongest evidence comes from the IMbrave150 trial, which established atezolizumab plus bevacizumab as the new first-line standard of care in advanced HCC, with promising signals also emerging in colorectal and gastric cancers (GC). Nevertheless, significant limitations persist, including overlapping toxicities, adaptive resistance mechanisms, and the lack of validated predictive biomarkers. In this regard, anti-VEGF plus ICI combination therapy offers substantial synergistic potential in GI malignancies. Future progress will depend on biomarker-driven patient selection, refined sequencing and dosing strategies, and rationally designed multi-modal regimens to maximize therapeutic benefit while minimizing harm.