Expression of IMPACT curtails metabolic plasticity and augments NK cell killing to abrogate metastatic growth

To form overt metastases, disseminated tumor cells must simultaneously acquire nutrients, circumvent oxidative stress, and evade organ-specific innate immune surveillance upon arrival. Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an in vivo cDNA screen using the mouse liver and KRASG12D/TP53R273H pancreatic cells to identify the RNA binding protein general control of amino acid synthesis 1-like 1 (GCN1) as integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the integrated stress response (ISR) to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of critical metabolites and to restore redox homeostasis. Alongside activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with an RNA binding protein (HNRNPK) to suppress the expression of MHC-I, antigen-presentation pathway molecules, and natural killer (NK) ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash robust NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade (ICB). Analysis of patient tumors demonstrates that elevated expression of GCN1 and HNRNPK with concomitant loss of IMPACT correlates with poor immunogenicity, aggressive behavior, and abbreviated survival. These studies provide novel insights linking tumor metabolism, immunity, and metastasis.