Inflammatory cytokines induce new cancer dependencies

Area of Science:

• Cancer Biology
• Immunology
• Genomics

Background:

• Tumor cells adapt to hostile environments, including inflammation from antitumor immunity and immune checkpoint blockade (ICB).
• Cytokine-induced changes in tumor cells may create unexplored vulnerabilities.
• Understanding these vulnerabilities is crucial for improving cancer therapies.

Purpose of the Study:

• To map inflammation-induced genetic vulnerabilities in cancer cells.
• To identify novel drug targets that enhance ICB efficacy.
• To explore the mechanisms by which tumor cells respond to inflammatory cytokines.

Main Methods:

• Performed in vitro genome-scale CRISPR loss-of-function screens in eight cancer models.
• Exposed cells to interferon-γ (IFNγ), interferon-β, or tumor necrosis factor.
• Integrated functional genomics, metabolomics, and pharmacologic perturbation.

Main Results:

• Identified the glycosylphosphatidylinositol (GPI) transamidase complex and the lipid phosphatase FITM2 as interferon-specific cancer dependencies.
• Tumor-specific deletion of GPI transamidase subunits or FITM2 significantly enhanced response to ICB in vivo.
• Loss of FITM2 sensitized cancer cells to IFNγ-driven endoplasmic reticulum and oxidative stress, leading to paraptosis-like cell death.

Conclusions:

• Discovered tumor-intrinsic dependencies on the GPI transamidase complex and FITM2 in response to inflammatory cytokines.
• Targeting these dependencies represents a potential strategy to overcome resistance to ICB.
• These findings offer new insights into tumor cell adaptation and vulnerability in the context of immunotherapy.