VDAC2 loss elicits tumour destruction and inflammation for cancer therapy.

ABSTRACT: Tumour cells often evade immune pressure exerted by CD8⁺ T cells or immunotherapies through mechanisms that are largely unclear^1,2. 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

SUBMITTER: Yuan S 

PROVIDER: S-EPMC12018455 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature