Abstract Immunotherapy has great potential to improve outcomes for breast cancer patients. Yet, deciding on how to rationally combine therapeutic agents and predict patient populations who would benefit remains challenging. Less than 20% of patients with metastatic breast cancer respond to current immunotherapy regiments, further demonstrating the need for research in this area. We postulate that oncogene activation leads to immune-related vulnerabilities which can be exploited to discover new immunotherapy combinations with improved efficacy. MYC is an oncogene that is frequently overexpressed in the majority of triple negative breast cancers (TNBCs), and is frequently found in disease recurrence, metastasis, and chemotherapy resistance. Despite the association of MYC with poor patient outcome, little is known about how MYC facilitates immune evasion in TNBC. Using TNBC patient datasets from the TCGA, we discovered that the MYC gene signature is anti-correlated with T-cell activation signatures and a subset of genes that regulate antigen processing and presentation with MHC-I. We further examined the effects of MYC using a MYC-driven mammary tumor mouse model (MTB-TOM). MYC activation leads to downregulation of MHC-I expression on tumor cells, poor CD8+ T cell infiltration and consequently poor response to anti-PD-L1 monotherapy. We demonstrate three methods to improve response to immunotherapy—by inactivation of MYC, by inducing an interferon response within the breast tumor, or by inducing MYC tumor synthetic lethality with a small molecule inhibitor of PIM kinases. Using these combination immunotherapy strategies, we observed that a majority of animals eradicated their breast tumors and demonstrated a durable anti-tumor response following subsequent tumor re-challenge. Our data suggest MYC is an indicator of whether a breast cancer patient will respond to immunotherapy. Analysis of the MYC gene signature as a predictor of patient response to pembrolizumab in combination with paclitaxel followed by AC in the neoadjuvant I-SPY 2 trial is on-going and will be presented. Our study is the first to describe oncogenic MYC downregulation of MHC-I in a TNBC model of breast cancer and to demonstrate translatable approaches to overcome MYC orchestrated immune evasion. Citation Format: Joyce V Lee, Filomena Housley, Christina Yau, Golzar Hemmati, Yibing Zhang, Susan Samson, Carole Baas, Hope Rugo, Mehrdad Matloubian, Andrei Goga. The MYC oncogene suppresses tumor immune infiltration and function which is reversible with combinatorial immunotherapies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-08.