Myokine signaling emerges as a central modifier of ICI-related colorectal injury in rectal cancer
Rectal cancer presents a particularly demanding immunologic setting for immune checkpoint inhibitors. Tumors in this anatomic site are not uniform in biology or behavior, and the surrounding microenvironment can either support treatment response or intensify tissue damage once immune activation accelerates. In dMMR/MSI-H rectal tumors, checkpoint blockade can produce strong anti-tumor activity. The same immune activation, however, can spill into the bowel wall and trigger ICI-associated colorectal injury, a toxic syndrome marked by diarrhea, mucosal ulceration, and, in severe cases, perforation.
The review places skeletal muscle far closer to this process than most oncologic discussions typically do. Muscle is not treated here as passive tissue under stress from cancer cachexia alone. It functions as an endocrine organ through myokines such as IL-6, IL-15, and irisin, forming a gut-muscle regulatory axis with direct relevance to intestinal inflammation and repair. The central idea is biologically plausible: systemic immune activation, mucosal injury, and loss of muscle mass can reinforce one another until bowel toxicity and sarcopenia become part of the same pathological loop.
A single checkpoint blockade response can therefore produce two opposing effects at once: tumor control on one side, and intestinal injury on the other.
CD8+ T cells, cytokine cascades, and barrier failure drive the toxic intestinal phenotype
The mechanism of ICI-related colorectal injury in this framework is not limited to a single inflammatory pathway. CD8+ T cell-mediated epithelial cytotoxicity sits at the center, but the injury profile widens quickly once the mucosal barrier begins to fail. Inflammatory cytokine cascades amplify tissue damage, gut dysbiosis increases endotoxin translocation, and microvascular hypoperfusion threatens oxygen delivery to already injured mucosa. Lactic acid accumulation and extracellular matrix fibrosis add another layer, suggesting that the process can evolve from acute inflammation into a more structurally entrenched form of injury.
This is clinically important because bowel toxicity in the ICI setting is not merely a symptom burden issue. Ulceration means epithelial discontinuity, and microvascular compromise means repair may be delayed even after immunosuppression begins. Fibrosis raises the possibility that repeated inflammatory episodes may leave the bowel less resilient over time. In rectal cancer, where local anatomy already complicates symptom assessment and mucosal healing, these overlapping pathways create a high-risk clinical environment.
IL-15 and irisin appear protective, while excess IL-6 may intensify intestinal inflammation
The review assigns different roles to individual myokines rather than treating them as a uniform signal class. IL-15 and irisin are framed as protective mediators that help preserve intestinal mucosa by restraining immunosuppressive cells. In contrast, excessive muscle-derived IL-6 is linked to increased intestinal inflammation. That divergence matters because it suggests skeletal muscle can either buffer or worsen gastrointestinal toxicity depending on the balance of its secreted signals.
The biological logic is straightforward. If myokine output helps regulate immune-cell composition in the gut, then muscle loss may strip away a protective influence at the same time inflammation is intensifying. Sarcopenia is no longer just a marker of frailty in this model; it becomes a contributor to the immunotoxic process itself. This creates a circular problem in which bowel injury worsens nutrition and mobility, muscle wasting alters inflammatory signaling, and the altered signaling further weakens mucosal defense.
The review links this axis to personalized rectal cancer immunotherapy by reframing muscle status as part of toxicity biology rather than an unrelated comorbidity.
Imaging and radiomics may make mucosal, vascular, and fibrotic injury more measurable
The review also turns to multimodal imaging, radiomics, and artificial intelligence as tools for quantitative monitoring. The practical appeal is clear: bowel injury under immune checkpoint therapy is heterogeneous, and visual impression alone may miss the full extent of mucosal, vascular, and fibrotic change. Imaging approaches that can detect these features more systematically could help clinicians follow injury trajectories rather than react only when symptoms become severe.
Radiomics adds another layer by extracting quantitative information from image patterns that may not be obvious on routine review. When combined with artificial intelligence, these methods are positioned as a way to classify lesion burden and perhaps distinguish inflammatory change from more fixed structural damage. In a disease state where diarrhea can reflect anything from early immune activation to deeper ulceration or hypoperfusion, that kind of stratification could be clinically useful. It may also help separate patients who need urgent immunosuppression from those who might benefit from closer surveillance and supportive care.
Stepwise immunosuppression, microbiota repair, and nutrition are positioned as a combined response
Management in this framework is deliberately multimodal. The review describes stepwise immunosuppression, microbiota reconstruction, metabolic support, and muscle-targeted exercise and nutrition as integrated strategies intended to interrupt the loop between sarcopenia and intestinal damage. No single intervention is presented as sufficient on its own. Instead, bowel inflammation, microbial disruption, and muscle depletion are treated as linked targets that require parallel attention.
That approach fits the pathobiology outlined in the article. If dysbiosis contributes to endotoxin translocation, then microbiota repair becomes more than symptomatic care. If muscle-derived signals influence immune tone, then maintaining skeletal muscle through nutrition and exercise may have value beyond preserving function. If inflammation has already produced mucosal ulceration, then immunosuppression must be balanced against the need to preserve antitumor efficacy in dMMR/MSI-H disease. Rectal cancer care already demands precision; checkpoint-related toxicity makes that precision harder, not less necessary.
Personalized immunotherapy will depend on matching antitumor benefit with gut safety
The review’s broader message is that rectal cancer immunotherapy cannot be judged solely by tumor response. Checkpoint blockade can be highly effective in biologically selected disease, but its benefits come with a real risk of colorectal injury when immune activation becomes excessive. Myokines offer one way to explain why some patients may tolerate therapy differently from others, especially if their muscle reserve, inflammatory tone, and gut barrier integrity are shifting at the same time.
What follows is a more integrated view of toxicity. Diarrhea, ulceration, microvascular compromise, dysbiosis, fibrosis, and sarcopenia are not separate silos in this model. They can interact as one disease process spreading across bowel, immune system, and skeletal muscle. The review argues for clinical strategies that monitor that network rather than any single organ in isolation.
The article does not claim that these pathways are fully settled. It instead provides a biologic framework for future work on how myokines, mucosal immunity, and treatment toxicity intersect in rectal cancer. The unresolved challenge is translating that framework into validated bedside markers that can predict injury before diarrhea, ulceration, or perforation forces treatment interruption.