Inflammatory cytokines induce novel cancer dependencies

Tumor cells respond and adapt to environmental stresses, including cytokine-mediated inflammation, to facilitate growth in hostile environments. However, cytokine responses also induce transcriptional and cell state changes that may predispose tumor cells to new vulnerabilities, which remain largely unexplored. Here, we performed in vitro genome-scale CRISPR loss-of-function screens in eight cancer models exposed to IFNγ, IFNβ, or TNFα to map context-specific genetic vulnerabilities. We identified members of the GPI transamidase complex and the lipid phosphatase FITM2 as interferon-specific cancer dependencies. Tumor-specific deletion of GPI transamidase subunits or FITM2 dramatically enhanced response to immune checkpoint blockade in vivo. By integrating functional genomics, metabolomics and pharmacological blockade, we determined that loss of FITM2 predisposed cancer cells to IFNγ-driven endoplasmic reticulum and oxidative stress, culminating in a paraptosis-like cell death. Our study provides a comprehensive profiling of tumor-intrinsic dependencies governing responses to inflammatory cytokines, thereby presenting promising avenues for therapeutic intervention.