T cell-mediated mechanisms of immune-related adverse events induced by immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs), which block inhibitory molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death protein 1 (PD-1) or programmed death protein ligand 1 (PD-L1), have revolutionized cancer therapy. While ICIs confer significant clinical benefits in numerous cancer patients, they also induce multi-organ immune-mediated toxicities, collectively termed immune-related adverse events (irAEs). This review aims to elucidate the role of T cell subsets in driving irAEs pathogenesis. Emerging evidence demonstrates that irAEs-affected tissues exhibit dysregulated T cell subset activity, characterized by autoreactive T cell activation, Treg imbalance, helper T cell and memory T cell dysfunction. Similar to classic autoimmune diseases, aberrant T cell subset activity plays a vital role in irAEs pathogenesis. By synthesizing recent advances in the contributions of diverse T cell subsets, this review establishes T cell subset dysregulation as a cardinal pathological feature of irAEs, offering insights into T cell-targeted biomarkers and therapies to mitigate toxicity without compromising antitumor immunity.