ABSTRACT: Checkpoint inhibitors targeting PD-1 and CTLA-4 have transformed cancer therapy. Both are genetically associated with autoimmune disorders. Moreover, certain immune-related adverse events and autoimmune risk variants are linked to the clinical efficacy of checkpoint inhibition. These associations suggest common principles governing successful cancer immunotherapy and autoimmune susceptibility. Here, we show that ablation of the cytosolic DNA exonuclease TREX1 predisposes mice to autoimmunity while promoting robust antitumor immunity. Constitutive TREX1 loss leads to early onset autoimmunity, characterized by multiorgan CD8+ T cell infiltration, myocarditis, and Sjgren's syndrome-like disease. In contrast, induced systemic TREX1 ablation is well tolerated and promotes effective CD8+ T cell-driven antitumor immunity. Detailed phenotypic studies revealed a notable overlap between productive antitumor and pathogenic autoimmune CD8+ T cell responses. Collectively, we provide mechanistic evidence for interrelated mechanisms underlying autoimmunity and successful cancer immunotherapy, uncover key parallels between adaptive T cell and innate immune checkpoints, and suggest that targeting autoimmune risk genes represents a promising future avenue for cancer immunotherapy.