CRTAM inhibition mitigates toxicity of immune checkpoint inhibitors without antitumor efficacy trade-off.

The benefit from immune checkpoint blockade (ICB) can be mitigated by the onset of immune-related adverse events (irAEs). The identification of checkpoints specific to irAEs could mitigate toxicity without antitumor efficacy trade-off. Here we integrated transcriptome and pharmacovigilance data to decipher the efficacy-toxicity equilibrium of ICB-regulated molecules and identified cytotoxic and regulatory T cell molecule (CRTAM) as an irAE checkpoint. Crtam knockout or T cell lineage-specific Crtam ablation impaired irAE induction in preclinical models. CRTAM⁺ T cells preferentially infiltrated normal tissues over tumors through the CRTAM-cell adhesion molecule 1 interaction and promoted interleukin 23-centered type 3 immunity. CRTAM inhibition preserved the 'hot' tumor microenvironment required for efficacy while mitigating toxicity in tumor-bearing irAE models. Quantification of the CRTAM-type 3 immune axis in blood samples enabled monitoring of irAEs in cohorts treated with ICB. Our study identifies CRTAM as a T cell checkpoint of irAEs, providing a potential target to uncouple efficacy from toxicity during immunotherapy.