Immune checkpoint inhibitors combined with VEGF/VEGFR-targeted therapy in microsatellite-stable advanced colorectal cancer: clinical advances and the potential for immune-sensitive tumor conversion

Abstract

Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide, and mismatch repair-proficient/microsatellite-stable (pMMR/MSS) tumors account for the majority of metastatic CRC cases. In contrast to dMMR/MSI-H CRC, pMMR/MSS tumors are typically characterized by low immunogenicity, limited neoantigen presentation, insufficient effector T-cell infiltration, and an immunosuppressive tumor microenvironment, which collectively restrict the efficacy of immune checkpoint inhibitor (ICI) monotherapy. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling contributes not only to abnormal angiogenesis but also to immune suppression by impairing dendritic-cell maturation, reducing immune-cell trafficking, promoting T-cell dysfunction, and facilitating the accumulation of immunosuppressive cell populations. These mechanisms provide a strong rationale for combining VEGF/VEGFR-targeted therapy with ICIs to normalize tumor vasculature and remodel the immune microenvironment. Clinical evidence for this strategy in advanced pMMR/MSS CRC remains heterogeneous. Treatment activity varies across therapeutic settings, antiangiogenic agents, and combination regimens, while many studies are limited by small sample sizes, single-arm designs, and substantial differences in patient characteristics. Emerging data suggest that metastatic pattern, molecular features, baseline immune contexture, and treatment line may influence clinical activity; however, no biomarker has yet been validated for routine patient selection. Multi-agent strategies may provide broader immune modulation but also increase toxicity, treatment complexity, and cost. This review summarizes the biological rationale, clinical efficacy, safety, and potential predictive factors of VEGF/VEGFR-targeted therapy combined with ICIs in advanced pMMR/MSS CRC. Particular emphasis is placed on the heterogeneity of clinical outcomes and on distinguishing mechanistic immune remodeling from the potential enhancement of tumor immune sensitivity. Future studies should prioritize biomarker-guided patient selection, randomized comparative trials, and comprehensive assessment of efficacy, safety, quality of life, and long-term clinical benefit.