Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

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.