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Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, 1 2 yet treatment resistance and immune-related adverse events (irAEs) in responders remain significant clinical challenges, and preclinical models remain limited.Methods To uncover mechanistic links between irAEs and ICI failure, we developed a novel murine model—Lifestyle-Induced Susceptibility to irAEs (LISA), which integrates diet-driven metabolic and microbial alterations to simulate human susceptibility to irAEs upon anti-PD-1 therapy. 3 4 This model faithfully recapitulates human disease in tissues impacted, susceptibility, severity, and treatment response.Results scRNA sequencing and flow cytometry analyses revealed tissue-specific expansion of inflammatory CD4 + and CD8+ tissue-resident memory T cells (Trms), marked by increased T-bet and Eomes expression, and a concurrent loss of reparative Trm subsets across impacted tissues, including the colon, liver, and skin. In contrast, tumors from the same mice exhibited a reciprocal immune profile, with reduction in cytotoxic Trms. These inflammatory signatures were strongly associated with an expansion of IFN-γ+ regulatory T cells (Tregs), which drove both systemic irAEs and reduced ICI efficacy.Dietary intervention restored Treg stability and prevented Trm reprogramming, thereby ameliorating both toxicity and therapeutic failure. Surprisingly, anti-LAG3 combination therapy enhanced both inflammatory and reparative Trms alongside IFN-γ+ Tregs, leading to improved tumor control without further aggravation of irAE symptoms. Finally, targeted deletion of IFN-γ or IFN-γ signaling specifically in Tregs (via Ifng L/L Foxp3 cre-YFP or Ifngr1 L/L Foxp3 cre-YFP) restored reparative Trms, suppressed inflammatory subsets, and significantly improved ICI response while reducing irAE incidence.Conclusions Our study reveals a novel immunoregulatory axis wherein IFN-γ-producing Tregs modulate tissue-resident T cell fate, thereby linking immune toxicity and resistance in ICI-treated hosts. These findings highlight the need for therapeutic strategies that balance Treg function and tissue inflammation to optimize immunotherapy outcomes.References Ferris RL, Blumenschein G, Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2023;375:1856–1867. 10.1056/NEJMoa1602252.Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutierrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med . 2022;386:24–34. 10.1056/NEJMoa2109970.Singh, RK, et al, Influence of diet on the gut microbiome and implications for human health. J Transl Med. 2017;15(1):73.Noverr MC, GB Huffnagle. Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 2004;12(12):562–8.Ethics Approval All animal experiments were performed in the American Association for the Accreditation of Laboratory Animal Care-accredited specific-pathogen-free facilities in the Division of Laboratory Animal Resources at the University of Pittsburgh School of Medicine (UPSOM). All animal protocols were approved by the Institutional Animal Care and Use Committees of the University of Pittsburgh.