In vivo CRISPR screens identify Mga as an immunotherapy target in triple-negative breast cancer

Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. We also provided a high-confidence valuable dataset for the understanding of tumor intrinsic immunomodulators and the discovery of novel anti-cancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances anti-tumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga functions through, at least partially, repression of MHC-II genes and related immune responses. Consistently, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-g signaling. Our findings provide new insights into tumor immune escape and pave the way for further exploration of MGA inhibition for clinical benefits in triple-negative breast cancer.