Chi F, Liu CB, Li J, Xia XW, Hua QJ, Wang W. Converting cold to hot: Strategies to sensitize microsatellite-stable colorectal cancer to immunotherapy. World J Gastrointest Oncol 2026; 18(5): 118319 [DOI: 10.4251/wjgo.v18.i5.118319]
Corresponding Author of This Article
Wei Wang, MD, Research Dean, Department of Interventional Oncology, Municipal Hospital Affiliated to Taizhou University, No. 581 Shifu Avenue East, Jiaojiang District, Taizhou 318000, Zhejiang Province, China. wangw@tzc.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
May 15, 2026 (publication date) through May 17, 2026
Times Cited of This Article
Times Cited (0)
Journal Information of This Article
Publication Name
World Journal of Gastrointestinal Oncology
ISSN
1948-5204
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Share the Article
Chi F, Liu CB, Li J, Xia XW, Hua QJ, Wang W. Converting cold to hot: Strategies to sensitize microsatellite-stable colorectal cancer to immunotherapy. World J Gastrointest Oncol 2026; 18(5): 118319 [DOI: 10.4251/wjgo.v18.i5.118319]
Feng Chi, Department of Gastrointestinal Surgery, Taizhou Hospital, Zhejiang University, Taizhou 317000, Zhejiang Province, China
Chi-Bo Liu, Department of Clinical Laboratory, Municipal Hospital Affiliated of Taizhou University, Taizhou 318000, Zhejiang Province, China
Jian Li, Xian-Wu Xia, Qian-Jin Hua, Wei Wang, Department of Interventional Oncology, Municipal Hospital Affiliated to Taizhou University, Taizhou 318000, Zhejiang Province, China
Co-first authors: Feng Chi and Chi-Bo Liu.
Co-corresponding authors: Qian-Jin Hua and Wei Wang.
Author contributions: Chi F and Wang W conceptualized and designed the study; Liu CB and Li J conducted the literature review, collected and analyzed relevant references, and contributed to the initial drafting of the manuscript; Xia XW designed and prepared the figures and tables; Hua QJ reviewed and revised the manuscript for intellectual content and finalized the manuscript for submission; Chi F and Liu CB contributed equally as co-first authors; all authors have read and approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Corresponding author: Wei Wang, MD, Research Dean, Department of Interventional Oncology, Municipal Hospital Affiliated to Taizhou University, No. 581 Shifu Avenue East, Jiaojiang District, Taizhou 318000, Zhejiang Province, China. wangw@tzc.edu.cn
Received: December 30, 2025 Revised: January 12, 2026 Accepted: February 9, 2026 Published online: May 15, 2026 Processing time: 136 Days and 7.4 Hours
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors (ICIs) have transformed outcomes for patients with microsatellite-instability-high or mismatch-repair-deficient CRC across disease stages, the vast majority of tumors are microsatellite-stable (MSS) or proficient mismatch repair and remain largely refractory to current immunotherapies. These “cold” tumors are characterized by low tumor mutational burden and neoantigen load, impaired antigen presentation, exclusion or dysfunction of cytotoxic T cells, and a profoundly immunosuppressive tumor microenvironment shaped by oncogenic signaling pathways, stromal components, and the gut microbiota. This review summarizes the immunobiology of MSS CRC and dissects key mechanisms of primary and acquired resistance to ICIs, including Wnt/β-catenin, mitogen-activated protein kinase and transforming growth factor-β signaling, myeloid-derived suppressor cells, regulatory T cells, angiogenic and metabolic reprogramming, and organ-specific immunity in liver and peritoneal metastases. We then discuss emerging strategies to convert MSS CRC from cold to hot disease, focusing on rational ICI-based combinations (chemotherapy, anti-vascular endothelial growth factor/vascular endothelial growth factor receptor, targeted agents, radiotherapy, dual checkpoint blockade), cancer vaccines, oncolytic viruses, adoptive cell therapies, microbiota-directed interventions, and loco-regional immunotherapy approaches. Finally, we highlight evolving biomarkers and trial designs that may enable precision immunotherapy for MSS CRC and outline future directions for translational research and clinical practice.
Core Tip: Most colorectal cancers are microsatellite-stable (MSS)/proficient mismatch repair and remain largely refractory to single-agent immune checkpoint inhibitors. This review dissects major resistance determinants low neoantigen burden, impaired antigen presentation, immune exclusion by cancer-associated fibroblast-rich stroma and abnormal vasculature, and myeloid-dominant suppression, particularly in liver metastases. We synthesize current evidence for rational “cold-to-hot” strategies, spanning chemo/radiotherapy priming, anti-angiogenic and anti-epidermal growth factor receptor regimens, mitogen-activated protein kinase/Wnt/transforming growth factor-β/CXCR4-signal transducer and activator of transcription 3 pathway targeting, and emerging vaccines, oncolytic viruses, cell therapies, and microbiome modulation. A biomarker-guided roadmap is proposed to personalize combination immunotherapy in MSS colorectal cancer.
