Abstract Immune checkpoint inhibitors targeting the negative regulators of T cell activation, PD-1 and CTLA-4, have transformed cancer therapy. Both targets are genetically associated with autoimmune disorders. Moreover, certain immune-related adverse events and autoimmune risk variants are linked to 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, similar to genetic loss of clinically validated T cell checkpoints, predisposes mice to autoimmunity while promoting robust antitumor immunity. Constitutive TREX1 loss leads to early onset autoimmunity, characterized by multi-organ CD8+ T cell infiltration, myocarditis and Sjögren’s syndrome-like disease. In contrast, induced systemic TREX1 ablation in adult mice is well tolerated and promotes effective CD8+ T cell-driven antitumor immunity. Detailed phenotypic studies revealed a striking 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 including TREX1 represents a promising future avenue for cancer immunotherapy. Citation Format: Lim, Junghyun, Williams, Katherine, Mittman, Stephanie, Rodriguez, Ryan, Ogasawara, Annie, Pacheco Sanchez, Patricia, Barnett, Grace, Cruz Tleugabulova, Mayra, Nabet, Barzin, Hung, Jeffrey, Marroquin, Kevin, Lau, Shari, Lee, Serena, Tyler, Paul, Carbone, Elizabeth, Hough, Bridget, Corpuz, Janice, Murota, Haruka, Dere, Edward, Shiffman, Smadar, Schutt, Leah, Gill, Herman, Lau, Julia, De Simone, Marco, Tam, Lucinda, Rosse-Girma, Merone, Warming, Soren, Oh, Soyoung, Rutz, Sascha, He, Meng Xiao, Muller, Soren, West, Nathaniel, Brewer, Thomas, Desai, Prashant, Williams, Simon, Ziai, James, Qu, Yan, Klaus Heger. Loss of the Autoimmune Risk Gene TREX1 Reveals a Convergence of Mechanisms Promoting Immune Tolerance Loss and Antitumor Immunity abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B072.
Lim et al. (Wed,) studied this question.