Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity
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ABSTRACT: The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK1 is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of NRF2-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by XBP1s downstream of ICD-induced endoplasmic reticulum stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or HMGCR inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampers ROS, ICD and therefore tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.
ORGANISM(S): Mus musculus
PROVIDER: GSE283933 | GEO | 2024/12/11
REPOSITORIES: GEO
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