Cancer Cell-Intrinsic Biosynthesis of Itaconate Promotes Tumor Immunogenicity

The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy. The Krebs cycle byproduct itaconate regulates immune cell function, however its role within tumor cells remains unclear. Here, cancer cell-intrinsic itaconate biosynthesis by cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) is shown to facilitate tumor immunogenicity and anti-tumor immunity.Cancer cell-intrinsic itaconate promotes tumor immunogenicity and T cell-dependent anti-tumor immunity.Cancer cell-intrinsic itaconate enhances TFEB-mediated lysosome biogenesis and antigen presentation.The mercury-based preservative thimerosal induces tumor IRG1 expression and itaconate production through a ROS-RIPK3-IRF1 axis.IRG1/itaconate induction in tumor cells by thimerosal sensitizes tumor responses to anti-PD1 immunotherapy in a mouse lymphoma model. Induction of the Krebs cycle-derived metabolite itaconate in cancer cells facilitates TFEB-mediated antigen presentation and anti-tumor immunity.