Gene expression profile at single cell level of 4T1 WT and Mga KO tumors derived on BALB/c mice

Immune evasion is critical for tumor initiation and progression, as well as determining the efficacy of immunotherapies. Through iterative in vivo CRISPR screens within seven syngeneic tumor models, we not only identified the core immune evasion pathways and context-dependent ones across cancer types but also provided a high-confidence valuable dataset for understanding tumor intrinsic immunomodulators and discovering 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 the tumor growth of TNBC model. Transcriptomics and single cell-RNA (sc-RNA) seq analyses revealed Mga function 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.