Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity
Liming Gui, Kaiwen Chen, Jingjing Yan, Ping Chen, Wei‐Qiang Gao, Bin Ma
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, NUAK family SNF1-like kinase 1 (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 nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by spliced form of X-box binding protein 1 (XBP1s) downstream of ICD-induced endoplasmic reticulum (ER) stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens 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. • NUAK1 inhibition induces tumor immunogenic cell death (ICD) • The XBP1s-activated mevalonate pathway is a negative feedback mechanism for ICD • Cholesterol attenuates ICD by reducing reactive oxidative species • Blockade of NUAK1 and the mevalonate pathway boosts antitumor immunity Gui et al. demonstrate that inhibiting NUAK1 triggers immunogenic cell death in tumors and activates the mevalonate-cholesterol pathway as a compensatory mechanism. Suppressing cholesterol synthesis amplifies the immunogenic cell death caused by NUAK1 inhibition. Furthermore, the synergistic use of a NUAK1 inhibitor with statins increases tumor sensitivity to anti-PD-1 therapy.