Tsai et al. showed that exposure to INFγ during early-stage T cell-mediated immunosurveillance remodeled the epigenetic and transcriptional landscape of the tumor cells to facilitate a switch from OXPHOS toward aerobic glycolysis, and promoted tumor immune evasion. The IFNγ–STAT3 signaling axis promoted cMyc-dependent metabolic reprogramming and resistance to senescence. In vivo CRISPR screening identified metabolic pathways regulating the antitumor immunity and identified Fasn and Slc23a2 as potential targets to suppress cMyc-mediated metabolic reprogramming and immune evasion.
Contributed by Shishir Pant
ABSTRACT: Immunoediting sculpts immunogenicity and thwarts host anti-tumor responses in tumor cells during tumorigenesis; however, it remains unknown whether metabolic programming of tumor cells can be guided by immunosurveillance. Here, we report that T cell-mediated immunosurveillance in early-stage tumorigenesis instructs c-Myc upregulation and metabolic reprogramming in tumor cells. This previously unexplored tumor-immune interaction is controlled by non-canonical interferon gamma (IFNγ)-STAT3 signaling and supports tumor immune evasion. Our findings uncover that immunoediting instructs deregulated bioenergetic programs in tumor cells to empower them to disarm the T cell-mediated immunosurveillance by imposing metabolic tug-of-war between tumor and infiltrating T cells and forming the suppressive tumor microenvironment.