biostudies-literatureZhu ZNCI NIH HHSNational Institutes of HealthNIH HHSNIGMS NIH HHSe2203718https://www.ebi.ac.uk/biostudies/studies/S-EPMC9875608biostudies-literatureUnknown10(3)STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Here, the authors report that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage-dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading toAdvanced science (Weinheim, Baden-Wurttemberg, Germany)STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.PMC9875608R01GM102413R01 CA243543R35 GM141833P30 CA016086R35GM141833R01 GM083024R01 GM102413R01GM083024Cloer EWZhu ZZhang JLiu PZhou XCook JGDotti GMei LSimon JMTan XMajor MBHepperla AJDu HWang YfalseSTING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.STING is an innate immune sensor for immune surveillance of viral/bacterial infection and maintenance of an immune-friendly microenvironment to prevent tumorigenesis. However, if and how STING exerts innate immunity-independent function remains elusive. Here, the authors report that STING expression is increased in renal cell carcinoma (RCC) patients and governs tumor growth through non-canonical innate immune signaling involving mitochondrial ROS maintenance and calcium homeostasis. Mitochondrial voltage-dependent anion channel VDAC2 is identified as a new STING binding partner. STING depletion potentiates VDAC2/GRP75-mediated MERC (mitochondria-ER contact) formation to increase mitochondrial ROS/calcium levels, impairs mitochondria function, and suppresses mTORC1/S6K signaling leading to2023-01-01T00:00:00Z2023 Jan2026-05-28T11:32:05.823Z2025-04-07T03:19:17.023ZS-EPMC98756083644506310.1002/advs.202203718