1. Academic Validation
  2. VDAC2 loss elicits tumour destruction and inflammation for cancer therapy

VDAC2 loss elicits tumour destruction and inflammation for cancer therapy

  • Nature. 2025 Mar 19. doi: 10.1038/s41586-025-08732-6.
Sujing Yuan # 1 Renqiang Sun # 1 Hao Shi 1 Nicole M Chapman 1 Haoran Hu 1 Cliff Guy 1 Sherri Rankin 1 Anil Kc 1 Gustavo Palacios 1 Xiaoxi Meng 1 Xiang Sun 1 Peipei Zhou 1 Xiaoyang Yang 2 Stephen Gottschalk 3 Hongbo Chi 4
Affiliations

Affiliations

  • 1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 2 Experimental Cellular Therapeutics Laboratory, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. hongbo.chi@stjude.org.
  • # Contributed equally.
Abstract

Tumour cells often evade immune pressure exerted by CD8+ T cells or immunotherapies through mechanisms that are largely unclear1,2. Here, using complementary in vivo and in vitro CRISPR-Cas9 genetic screens to target metabolic factors, we established voltage-dependent anion channel 2 (VDAC2) as an immune signal-dependent checkpoint that curtails interferon-γ (IFNγ)-mediated tumour destruction and inflammatory reprogramming of the tumour microenvironment. Targeting VDAC2 in tumour cells enabled IFNγ-induced cell death and cGAS-STING activation, and markedly improved anti-tumour effects and immunotherapeutic responses. Using a genome-scale genetic interaction screen, we identified Bak as the mediator of VDAC2-deficiency-induced effects. Mechanistically, IFNγ stimulation increased Bim, BID and Bak expression, with VDAC2 deficiency eliciting uncontrolled IFNγ-induced Bak activation and mitochondrial damage. Consequently, mitochondrial DNA was aberrantly released into the cytosol and triggered robust activation of cGAS-STING signalling and type I IFN response. Importantly, co-deletion of STING signalling components dampened the therapeutic effects of VDAC2 depletion in tumour cells, suggesting that targeting VDAC2 integrates CD8+ T cell- and IFNγ-mediated adaptive immunity with a tumour-intrinsic innate immune-like response. Together, our findings reveal VDAC2 as a dual-action target to overcome tumour immune evasion and establish the importance of coordinately destructing and inflaming tumours to enable efficacious Cancer Immunotherapy.

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