Targeting VDAC1 to induce mitochondrial DNA–STING signaling and lysosomal cell death in T-cell lymphoma

Abstract The study investigates the crosstalk between mitochondria and Stimulator of Interferon Genes (STING) signaling in T-cell lymphoma (TCL), revealing a lysosome-dependent mechanism for cell death. STING expression in TCL is abnormally high compared to normal T cells, potentially driven by activated immune dysregulation or oncogenic stress. STING is involved in cytosolic DNA sensing through canonical cGAS–STING–IRF3 axis whereby it not only induces type I interferon (IFN-I) responses but also mediates its subsequent trafficking to lysosomal compartments which leads to lysosomal membrane permeabilization (LMP)-mediated non-canonical cell death. Notably, we revealed that mitochondrial dysfunction and metabolic reprogramming promoted STING-induced killing of TCL cells. Voltage dependent anion channel 1 (VDAC1), a pore-forming protein on the mitochondrial outer membrane. Functionally, the oligomerization of VDAC1 which induced by mitochondrial dysfunction resulted in the creation of large non-selective pores that allowed for cytosolic access and release into from mitochondria DNA (mtDNA). The released mtDNA acted as an endogenous ligand for cGAS to initiate the STING activation, IRF3 phosphorylation and subsequent ISGs expression. Pharmacological modulation of VDAC1 changed mtDNA efflux and STING activation, indicating its status as a druggable upstream regulator. Targeting VDAC1 to control mitochondrial membrane permeability may represent a novel strategy to potentiate STING-dependent cytotoxicity in malignant T cells. Moreover, activated STING subsequently translocated to lysosomes, where it induced LMP and triggered the release of cathepsins and other hydrolases, promoting protease-mediated cell death pathways. Accordingly, mitochondria are a dynamic hub that integrates metabolic stress with innate immune signaling, directly linking to lysosome-dependent cellular death by way of the VDAC1–STING axis. Our research reveals VDAC1-dependent release of mtDNA and STING activation to be a novel therapeutic strategy that can be exploited for eliminating malignant T cells.