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

Background Inadequate tumor cell-intrinsic interferon response leads to limited efficacy of immune checkpoint blockade (ICB) therapy, such as anti-PD-1. Cholesterol metabolism can sharply regulate anti-tumor immune response. However, the mechanism of cholesterol synthesis affects the tumor cell-intrinsic interferon response in microsatellite instability (MSI) colorectal cancer (CRC) remains unclear. Method Small interfering RNA(siRNA) libraries and GSEA enrichment analysis are employed to screen out the key molecular which affects the tumor cell-intrinsic interferon response in MSI CRC. Mass cytometry and multiple immunofluorescence (mIF) for detecting changes in tumor micro-environment. The confocal immunofluorescence (IF), truncated protein construction, and co-immunoprecipitation (co-IP) were utilized to investigate the mechanism. The efficacy of immunotherapy were assessed in subcutaneous transplantation tumor models and human peripheral blood mononuclear cells-patient derived xenografts(hPBMC-PDX) models. Results Using the siRNA library and GSEA analysis, we revealed that mevalonate kinase (MVK) notably impairs the tumor cell-intrinsic interferon response in MSI CRC cells. After MVK gene knockout, the levels of Th1 type chemokines (CXCL9 and CXCL10) and the abundance of CD8 ⁺ T cells were increased in tumor, and tumor growth was significantly slowed in mice with intact immune systems. Mechanistically, MVK interacts with the transcriptional activation domain (TAD) of signal transducer and activator of transcription 1 (STAT1), a key transcription factor in the interferon response. This interaction leads to reduced nuclear translocation of STAT1, ultimately impacting interferon reactivity. In the analysis of the hPBMC-PDX model and the MSI CRC clinical cohort, we observed that a low level of MVK in tumors is associated with a significant efficacy of anti-PD-1 therapy. Conclusion MVK is the crucial medium in the cholesterol metabolism to inhibit the tumor cell-intrinsic interferon response of tumor cells. Moreover, targeting MVK is promising to increase the efficacy of ICB therapy by increasing the interferon response in MSI CRC.