Immune checkpoint blockade has transformed cancer therapy, but immune-related adverse events (irAEs) remain a major, sometimes fatal, limitation, and the lack of robust preclinical models has hindered mechanistic insight. We present the lifestyle-induced susceptibility to irAEs (LISA) model, in which diet-driven metabolic and microbial alterations recreate human-like susceptibility to anti-PD-1 toxicity. LISA recapitulates multi-organ irAEs with immune infiltration and cytokine production, severity depending on sex, age, treatment modality, and immunotherapy response. Mechanistically, dysbiosis marked by Akkermansia muciniphila enrichment accompanies aberrant immune activation, driving regulatory T cell (Treg) fragility and CD8+ cytotoxic effector populations, both observed in patients with irColitis. Dietary reversal, metabolite supplementation, and blocking interferon (IFN)-γ production or signaling in Tregs restored Treg stability and resolved inflammation.
