Abstract 7401: STING proton channel function controls T cell survival and tumor immune evasion

Abstract Background The cGAS-STING pathway is a central sensor of cytosolic DNA that activates type I interferon (IFN-I) responses. In cancer, cGAS-STING signaling can promote antitumor immunity by enhancing antigen presentation and T cell priming. However, intrinsic STING activation in T cells also triggers T cell death within the tumor microenvironment in an IFN-independent manner, thereby limiting antitumor T cell immunity. The precise mechanisms underlying this dichotomous behavior remain unknown. Recent work has revealed that, beyond its canonical role in IFN induction, STING also acts as a proton channel that mediates IFN-independent processes such as autophagy, lysosome biogenesis, and cell death. Yet the physiological relevance of STING proton channel in vivo—particularly in shaping T cell fate in tumors—has remained unclear due to the lack of genetic models that selectively disrupt it. Methods We performed targeted mutagenesis of conserved residues in mouse and human STING to identify mutations that selectively abolish proton channel activity while preserving IFN-I signaling. The effects of the mutations on STING trafficking, signaling, autophagy induction, and antiviral responses were evaluated using biochemical assays, imaging, and flow cytometry. To define the physiological role of STING’s proton channel in vivo, we generated a knock-in mouse model carrying the channel mutation. T cell death and antitumor function were assessed using syngeneic tumor models. Results We identified a conserved STING mutation in mouse and human that eliminated proton channel activity and Golgi deacidification while preserving STING trafficking, TBK1-IRF3 activation, and IFN-I induction. Functional assays revealed that the channel mutation abolished STING-mediated autophagy, lysosome biogenesis, and impaired antiviral defense. Splenic T cells from the channel-deficient-STING knock-in mice lost channel-dependent activities and were resistant to STING-induced cell death in vitro. In vivo, STING channel deficiency protected CD8+ T cells from STING-driven cell death in an IFN-independent manner. We further showed that STING channel deficiency enhanced T cell persistence in the tumor microenvironment and significantly reduced tumor growth in the MC38 colon adenocarcinoma model, demonstrating a previously unrecognized role for the STING proton channel in modulating T cell survival and antitumor immunity. Conclusions We establish the first genetic model that selectively disrupts STING proton channel activity while preserving IFN-I signaling. This model uncovers a critical IFN-independent role for the STING proton channel in driving T cell death and promoting tumor immune evasion. Our findings demonstrate distinct, separable outputs of STING signaling and identify the proton channel activity of STING as a potential therapeutic target to improve T cell-mediated antitumor immunity. Citation Format: Cong Xing, Kun Song, Zhen Tang, Antonina Araszkiewicz, Nicole Dobbs, Wanwan Huai, Nan Yan. STING proton channel function controls T cell survival and tumor immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7401.