Abstract Immune checkpoint blockade-induced immune-related adverse events (irAEs) hamper the application of this revolutionary anti-tumor therapeutic strategy. Here, we explored the mechanisms driving irAEs by profiling the immune ecosystem of major irAE-affected organs at the single-cell scale. The analysis identified three populations of cytotoxic T lymphocytes that mediate anti-tumor immunity (CTL1) or that induce irAE in the gut (CTLirAE-I) or in multiple other organs (CTLirAE-II). Interleukin-JAK1 signaling was specifically activated in the CTLirAE-II population upon PD-1 blockade. Targeting JAK1 remarkably relieved the irAEs in the heart and lung, without compromising the anti-tumor efficacy. Tracking TCR sequence and transcriptome showed that CTLirAE-II and CTL1 populations originated from lymph node progenitor cells, while the CTLirAE-I population was derived from tissue-resident memory T cells. Moreover, irAEs could be monitored by assessing the CTLirAE-II population in circulation. In conclusion, this study elucidates the landscape of cellular changes in irAEs across multiple organs following immunotherapy and proposes strategies for relieving irAE symptoms and facilitating diagnosis.
Liu et al. (2026) studied this question.