Immune Checkpoint Inhibitors Induce Intestinal Epithelial Injury and a Senescence‐Like Phenotype

ABSTRACT Immune checkpoint inhibitors (ICIs) have significantly improved survival rates in cancer patients, yet their administration is frequently linked to serious adverse events, particularly colitis. Notably, ICI‐induced colitis demonstrates pathological characteristics distinct from those of conventional forms of colitis. To investigate this, we developed an ICI‐mediated gut injury model across multiple mouse strains and examined clinical specimens. Epithelial damage was evaluated via H&E and immunofluorescence staining, with phenotypes further validated through reanalysis of single‐cell RNA‐seq data, qPCR, and bulk mRNA sequencing. Initial observations in intestinal biopsies from ICI‐colitis patients revealed severe epithelial injury and extensive immune cell infiltration. Reanalysis of single‐cell RNA sequencing data from these patients indicated a pronounced expansion of effector and cycling CD4 + /CD8 + T cell subsets, along with upregulated inflammatory cytokine signatures. These clinical observations were replicated in several colitis‐susceptible mouse models, which displayed both systemic and local immune cell expansion, prominent intestinal CD8 + T cell infiltration, and subsequent epithelial damage‐including disruption of the tight junction proteins ZO‐1 and Occludin. Further analysis in these models showed a significant reduction in specialized secretory cells, such as goblet, tuft, and enteroendocrine cells. Prolonged ICI treatment in C57BL/6 mice not only corroborated epithelial injury but also elicited a premature senescence phenotype, indicating profound and persistent intestinal functional impairment. Collectively, this study demonstrates that ICI treatment induces severe intestinal epithelial damage in mice, characterized by barrier dysfunction, loss of secretory cells, and the onset of cellular senescence. Our results underscore accelerated tissue aging as a novel pathological outcome of ICI therapy, providing new perspectives for managing immune‐related adverse events.