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Background Immune checkpoint inhibitors (ICIs) are first-line treatment options for many advanced malignancies and are increasingly being deployed in early-stage disease. Despite their clinical success, responses to ICI treatment remain idiosyncratic and are often hindered by the development of treatment-limiting side effects, termed immune-related adverse events (irAEs). Notably, irAEs can impact nearly every organ system, leading to significant morbidity, risk of hospitalization, discontinuation of potentially cancer-curing treatments, and in some cases even death. Anti-irAE treatments often consist of broad immunosuppressive agents, such as corticosteroids and cytokine inhibitors, which have been shown to potentially disrupt survival benefit for patients with cancer receiving ICI treatment. Current preclinical systems rarely allow for simultaneous assessment of anti-tumor immunity and autoimmunity. This highlights the need for modeling approaches that exploit diverse host immune responses and susceptibility to irAEs alongside differences in tumorgenicity to capture the breadth of clinical conditions.Methods To recapitulate the etiology by which irAEs are initiated in patients with cancer, we utilized a unique series of syngeneic, transplantable tumor cell lines in autoimmune-prone non-obese diabetic (NOD) mice. We assessed whether distinct expression patterns of immunoregulatory receptors in the tumor microenvironment (TME) compared to the site of ICI-induced irAEs could evoke tissue-specific responses and whether these differences may lead to identification of actionable targets for anti-irAE treatments.Results We determined that tumor necrosis factor receptor 2 (TNFR2) was differentially expressed in T cells derived from irAE-susceptible pancreatic islets compared to tumor, suggesting the potential for a therapeutic window to inhibit irAEs without impacting tumor control. In particular, CD8 + T cells expressed TNFR2 within the TME but not pancreatic islets, whereas Tregs highly expressed TNFR2 in both tissue compartments. We posited, and observed, that we could exploit this differential expression by administering a TNFR2 agonist (NewSTAR2), to promote expansion of immunosuppressive Tregs to protect against anti-PD-1-induced irAEs, but in the tumor also engage CD8+ T cells, leading to equivalent tumor control. In the TME, TNFR2 agonism expanded CD4+Foxp3+ T cells, yet they displayed decreased expression of CD25 and TIM3 indicative of reduced immunosuppression, which may also assist in potentiating ICI efficacy.Conclusions We have successfully used this novel proof-of-concept mouse model to identify that TNFR2 agonism limits irAEs without impacting tumor control. This highlights an exciting treatment strategy for clinical consideration and provides a framework to define novel anti-irAE targets that can reduce ICI-induced immunotoxicity without abrogating tumor control.