Home›Gastroenterology› Immune checkpoint inhibitors in rectal cancer: balancing anti-tumor effects against ICI-associated colorectal injury
Immune checkpoint inhibitors in rectal cancer: balancing anti-tumor effects against ICI-associated colorectal injuryImmune drugs for rectal cancer can cause intestinal damage
Frontiers in MedicinePublished August 20, 2026Study authors: Shuang Ma, Jinxue Rong, Xinwei Wu, Xiaolin Wu, Yibo Gao, Huixian Li, Tao YanDOI ↗Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease
AI-generated summary of the cited source, checked by automated accuracy review.
How we work
Share
Key Takeaway
Consider monitoring for ICI-associated colorectal injury in rectal cancer patients, especially those with dMMR/MSI-H tumors.
This systematic review synthesizes current evidence on immune checkpoint inhibitors (ICIs) in rectal cancer, focusing on their dual impact: robust anti-tumor effects on dMMR/MSI-H rectal tumors and the potential for overactivated immunity to cause ICI-associated colorectal injury (ICI-CRI). The review does not report pooled effect sizes or specific trial data; instead, it integrates mechanistic insights and clinical observations to outline a framework for managing gastrointestinal toxicity.
Key findings include the role of myokines in a gut-muscle regulatory axis. Specifically, IL-15 and irisin appear to protect intestinal mucosa by restraining immunosuppressive cells, while excess muscle-derived IL-6 amplifies intestinal inflammation. These mechanisms are proposed to underlie ICI-CRI, which is characterized by diarrhea, mucosal ulceration, and perforation.
The authors suggest a myokine-centered regulatory network to maximize ICI efficacy while reducing gastrointestinal toxicity. They propose stratified management strategies including immunosuppression, microbiota reconstruction, metabolic support, and muscle-targeted exercise or nutrition. However, these are theoretical references rather than validated clinical protocols.
Limitations are not explicitly reported in the source, but the review's conclusions are based on mechanistic reasoning and early observations, not clinical trial outcomes. The authors do not provide quantitative effect sizes or patient-level data.
For clinicians, this review underscores the need to balance ICI benefits against potential gastrointestinal adverse events in rectal cancer, particularly in dMMR/MSI-H tumors. It highlights the importance of monitoring for ICI-CRI and considering supportive strategies, but these recommendations should be interpreted cautiously until further clinical validation.
How this fits prior evidence
This systematic review extends prior coverage by focusing on the gastrointestinal toxicity of immune checkpoint inhibitors (ICIs) in rectal cancer, a specific adverse event not detailed in earlier reports. While prior items noted ICI efficacy in other cancers (e.g., improved pathological complete response in triple-negative breast cancer, overall survival benefit in extensive-stage small-cell lung cancer), this review addresses the mechanistic basis of ICI-associated colorectal injury and proposes a myokine-centered management framework. It contrasts with the limited activity seen in unselected pancreatic ductal adenocarcinoma, emphasizing that benefit is confined to dMMR/MSI-H rectal tumors. The review also aligns with the early synergy seen with polysaccharide combinations, but stresses that these are theoretical strategies requiring validation.
Treating rectal cancer with immune checkpoint inhibitors can be a double-edged sword. While these drugs are very effective at attacking tumors, they can also overactivate the immune system. This often leads to intestinal inflammation and tissue damage known as ICI-associated colorectal injury.
Researchers looked into how specific proteins, called myokines, influence this balance. They found that certain proteins like IL-15 and irisin help protect the gut lining by keeping harmful cells in check. On the other hand, an excess of a different protein called IL-6 can make intestinal inflammation worse for patients.
Because these findings are based on theoretical models rather than direct clinical trials, we do not yet know how to apply them in every case. However, they offer a roadmap for future treatments. Doctors may eventually use these targets to help patients stay on their cancer medications while reducing painful side effects like diarrhea or tissue ulcers.
What this means for you:
Certain gut proteins may help protect the intestinal lining from damage caused by rectal cancer treatments.
Common questions
What are the side effects of these cancer drugs?
Patients receiving immune checkpoint inhibitors for rectal cancer may experience a condition called ICI-associated colorectal injury. This can cause problems like diarrhea, mucosal ulceration, and perforation of the intestinal tissue.
How do certain proteins affect treatment safety?
Two specific proteins, IL-15 and irisin, help protect the gut lining by restraining cells that suppress the immune system. In contrast, too much of a protein called IL-6 can increase inflammation in the intestines.
Is this new treatment ready for everyone?
The current findings are based on theoretical mechanisms rather than clinical trial data. While they offer a path toward better management of side effects, you should talk to your doctor about your specific treatment plan.
Rectal cancer exhibits prominent anatomical and molecular heterogeneity, shaping a tumor microenvironment that determines responsiveness to immune checkpoint inhibitors (ICIs). Though ICIs exert robust anti-tumor effects on dMMR/MSI-H rectal tumors, overactivated immunity causes ICI-associated colorectal injury (ICI-CRI) characterized by diarrhea, mucosal ulceration and even perforation. Its pathological mechanisms cover CD8+ T cell-mediated epithelial cytotoxicity, inflammatory cytokine cascades, gut dysbiosis-induced endotoxin translocation, microvascular hypoperfusion, lactic acid accumulation and extracellular matrix fibrosis. Skeletal muscle-secreted myokines (IL-6, IL-15, irisin) form a critical gut-muscle regulatory axis: IL-15 and irisin protect intestinal mucosa by restraining immunosuppressive cells, while excess muscle-derived IL-6 amplifies intestinal inflammation. Multimodal imaging combined with radiomics and artificial intelligence realizes quantitative monitoring of mucosal, vascular and fibrotic lesions. Stratified management schemes including stepwise immunosuppression, microbiota reconstruction, metabolic support and muscle-targeted exercise/nutrition can interrupt the vicious loop linking sarcopenia and intestinal damage. This review systematically illustrates the myokine-centered regulatory network, providing theoretical references to maximize ICI efficacy while reducing gastrointestinal toxicity for personalized rectal cancer immunotherapy.
