Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune -related adverse effects including colitis. CPI -induced colitis is hallmarked by expansion of resident mucosal IFNg cytotoxic CD8 + T cells, but how these arise is unclear. Here, we track CPI -bound T cells in intestinal tissue using multimodal single -cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug -bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI -bound cells were largely CD4 + T cells, including enrichment in CPI -bound peripheral helper, follicular helper, and regulatory T cells. IFNg CD8 + T cells emerged from both tissue -resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co -localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.