Co-culture CRISPR screens reveal ATG9A as a regulator to macrophage-mediated cytotoxicity in cancer

This study investigates the role of cancer cell surface proteins in modulating the response of cancer cells to macrophage-induced cytotoxicity. Utilizing two targeted CRISPR screens using OVCAR-8 cell line and a targeted CRISPR library for cancer cell surface proteins, ATG9A was identified as a key regulator. ATG9A KO increased the sensitivity of cancer cells to macrophage-induced cytotoxicity. Subsequent surface and whole-cell mass spectrometry analysis elucidated the underlying mechanisms; ATG9A KO in cancer cells not only enhances macrophage infiltration and activation but also plays a crucial role in the plasma membrane repair following macrophage co-culture. These findings reveal novel targets for enhancing macrophage-mediated cytotoxicity in cancer, offering additional avenues for therapeutic intervention.