STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity

Adv Sci (Weinh). 2023 Jan;10(3):e2203718. doi: 10.1002/advs.202203718. Epub 2022 Nov 29.


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 to RCC growth retardation. STING interaction with VDAC2 occurs through STING-C88/C91 palmitoylation and inhibiting STING palmitoyl-transferases ZDHHCs by 2-BP significantly impedes RCC cell growth alone or in combination with sorafenib. Together, these studies reveal an innate immunity-independent function of STING in regulating mitochondrial function and growth in RCC, providing a rationale to target the STING/VDAC2 interaction in treating RCC.

Keywords: 2-BP; STING; VDAC2; innate immunity-independent; mTORC1; mitochondrial homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium / metabolism
  • Carcinoma, Renal Cell* / metabolism
  • Humans
  • Immunity, Innate
  • Kidney Neoplasms*
  • Mitochondria / metabolism
  • Reactive Oxygen Species / metabolism
  • Tumor Microenvironment
  • Voltage-Dependent Anion Channel 2 / metabolism


  • Calcium
  • Reactive Oxygen Species
  • VDAC2 protein, human
  • Voltage-Dependent Anion Channel 2