Inflammatory cytokines induce novel cancer dependencies

Abstract

Tumor cells respond and adapt to environmental stresses such as cytokine-mediated inflammation, triggered by anti-tumor immunity and enhanced by immune checkpoint blockade. While these adaptations promote tumor survival, they also induce transcriptional, metabolic and cellular state changes that create exploitable vulnerabilities. To map these inflammation-induced synthetic lethalities, we performed in vitro genome-scale CRISPR loss-of-function screens across eight murine and eight human cancer models exposed to IFNγ, IFNβ, or TNFα. Our study revealed that cytokine dependencies in cancers align with evolutionarily conserved pathways, including antiviral signaling, autophagy, vacuolar protein sorting, and peroxisome biogenesis. Unexpectedly, we identified novel roles for the ER enzymes glycosylphosphatidylinositol (GPI) transamidase and lipid phosphatase FITM2 in restricting interferon-driven stress responses. Loss of these enzymes in tumors triggered innate sensitivity to interferons in vitro , and enhanced responses to immune checkpoint blockade in vivo . Using genome-interaction screens, metabolomics and pharmacological inhibitors, we uncovered the molecular mechanisms by which the GPI transamidase and FITM2 sensitized tumors to IFNs. Specifically, tumors lacking GPI transamidase activity initiated an antiviral response mediated by the molecule tetherin, leading to cell death. Similarly, FITM2 loss disrupted lipid homeostasis, sensitizing tumor cells to innate intracellular defense molecules known as interferon-inducible GTPases. These GTPases orchestrated a series of cellular stresses — ER stress, oxidative stress, and autophagy — culminating in a distinct form of cell death termed paraptosis. Our findings thus provide a broad resource of tumor-intrinsic adaptations to inflammation, which can be exploited to overcome immune evasion or directly eliminate tumors.