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
4 affiliations
- 1School of Pharmaceutical Sciences, Wenzhou Medical University
- 2Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences
- 3Department of Colorectal Medicine, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences
- 4Zhejiang Key Laboratory of Functional Nucleic Acids for Basic and Clinical Application of Sciences
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.
Related
- Multimodal Immune Profile Score (IPS) as a Pan-Cancer Biomarker for Stratifying Outcomes of Immune Checkpoint Inhibitor Benefit in Microsatellite Stable Colorectal Cancer and Rare Solid Tumors
- Conversion Surgery After HAIC-Based Combination Therapy with Targeted Therapy and Immune Checkpoint Inhibitors for Initially Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study
- Lipid metabolism: a potential checkpoint for cGAS-STING regulation in colorectal cancer
- Mechanisms of immune resistance in microsatellite-stable colorectal cancer
- CXCR2 associated neutrophil stromal interactions and immune exclusion in microsatellite stable colorectal cancer
BibTeX
@article{wang2026immune,
title = {{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}},
author = {Ruoxin Wang and Xiaofang Zhou and Meiqin Yuan and Zeng Wang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1962600},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1962600/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - 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
AU - Ruoxin Wang
AU - Xiaofang Zhou
AU - Meiqin Yuan
AU - Zeng Wang
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1962600
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1962600/full
AB - 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.
SN - 1664-3224
ER -