Mevalonate kinase inhibits anti-tumor immunity by impairing the tumor cell-intrinsic interferon response in microsatellite instability colorectal cancer.

Insufficient tumor cell-intrinsic interferon response represents a major obstacle in immune checkpoint blockade (ICB) therapy, particularly in anti-PD-1 treatment. Although cholesterol metabolism has been demonstrated to be a critical regulator of anti-tumor immune responses, whether cholesterol influences tumor cell-intrinsic interferon response in microsatellite instability (MSI) colorectal cancer (CRC) remains unknown. Through comprehensive siRNA library screening and Gene Set Enrichment Analysis (GSEA), we identified mevalonate kinase (MVK) as a crucial negative regulator of tumor cell-intrinsic interferon response in MSI CRC cells. Genetic ablation of MVK resulted in significant upregulation of Th1 type chemokines (CXCL9 and CXCL10) and enhanced CD8T cell infiltration in MSI CRC, consequently leading to marked tumor growth suppression in immunocompetent mice. At the molecular level, we demonstrated that MVK physically interacts with the transcriptional activation domain (TAD) of signal transducer and activator of transcription 1 (STAT1). This interaction substantially impairs STAT1 nuclear translocation, thereby attenuating interferon signaling cascade. Furthermore, analyses of humanized PBMC-PDX models and clinical cohorts of MSI CRC patients revealed that reduced MVK expression in tumor tissues strongly correlates with favorable responses to anti-PD-1 therapy. Collectively, our findings establish MVK as a pivotal mediator in cholesterol synthesis pathway that negatively regulates tumor cell-intrinsic interferon response in MSI CRC. These results suggest that therapeutic targeting of MVK represents a promising strategy to enhance ICB efficacy through potentiation of interferon responses in MSI CRC patients.