Radiation-induced intestinal injury (RIII) is a prevalent and devastating complication in patients with pelvic and abdominal tumors following radiotherapy. The pathological hallmark of RIII involves the depletion of Lgr5 + intestinal stem cells (ISCs), disruption of the intestinal mucosal barrier, gut microbiota dysbiosis, and uncontrolled inflammatory cascades, which not only severely impair patients′ quality of life but also limit the efficacy of radiotherapy. Interleukin-22 (IL-22), a member of the IL-10 cytokine family, has emerged as a promising candidate due to its unique epithelia-targeting protective properties, which is distinct from most other cytokines. This review aims to systematically synthesize the biological characteristics of IL-22, its multifaceted roles and underlying mechanisms in RIII, and to discuss the challenges and prospects of its clinical translation, providing a comprehensive foundation for future research and therapeutic development. IL-22 serves as a critical bridge connecting immune regulation and epithelial repair, holding great promise for the treatment of RIII. Through mechanism-driven innovations in delivery systems, biomarker-guided precision medicine, and synergistic combination therapies, the protective effects of IL-22 can be maximized while mitigating potential risks, paving the way for its successful clinical translation to improve the outcomes of patients with RIII. In the context of RIII, IL-22 exerts multiple protective effects through distinct mechanisms. Firstly, it serves as a core protector of Lgr5+ ISCs, the cornerstone of intestinal epithelial homeostasis and regeneration. Secondly, IL-22 plays a pivotal role in repairing radiation-damaged intestinal mucosal barriers. It promotes the secretion of mucins from goblet cells to reinforce the mucus layer, upregulates the expression of tight junction proteins (ZO-1 and Occludin) to reduce intestinal permeability. Thirdly, IL-22 inhibits inflammatory response in RIII while its long-term or excessive activation may increase the risk of malignant cancer. Fourthly, IL-22 engages in bidirectional crosstalk with the gut microbiota. Despite its significant therapeutic potential, the clinical translation of IL-22 for RIII faces several challenges: the administration of IL-22 may cause off-target effects and systemic inflammation; sustained activation of the STAT3 pathway may promote the proliferation of residual tumor cells; the complex crosstalk between IL-22 and other immune factors in the radiotherapy microenvironment remains unclear. To address these issues, future research should focus on: developing targeted delivery systems to achieve site-specific enrichment of IL-22; establishing a biomarker system integrating multi-omics data to predict treatment response and guide personalized medicine; and exploring microbiota-immune combination strategies to synergistically enhance endogenous IL-22 function. Additionally, rigorous safety evaluations in tumor models are essential to define the safe window of IL-22 application and avoid potential carcinogenic risks.
ZHU et al. (Thu,) studied this question.