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, there remains a dearth of ICD-inducing targets. Employing kinome-wide CRISPR-Cas9 screening, we have identified NUAK1 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 NUAK1 inhibition-induced endoplasmic reticulum stress, functions as negative feedback on ICD. Targeting the mevalonate pathway using HMGCR inhibitor statins amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol mitigates ICD by diminishing ROS. The combination of NUAK1 inhibitors and statins enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate pathway in conjunction with ICD-targeted immunotherapies such as NUAK1 inhibition.