PROJECT SUMMARY/ABSTRACT Blockade of the PD-1/PD-L1 immune checkpoint has advanced the treatment of patients with diverse types of solid tumors. However, PD-1/PD-L1 blockade has been limited by low response rates and limited durations of response in certain settings, such as non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), as well as ovarian, prostate and colorectal cancers. These findings are explained, at least in part, by the premise that the PD-1/PD-L1 axis is only one of a number of tumor immune suppressive mechanisms that require inhibition. Therefore, additional strategies are clearly needed to improve the immunotherapy of human cancers. In this respect, cancer cells activate a program of immune evasion involving, for example, induction of PD-L1 expression and the downregulation of effectors that promote innate and adaptive immune response. The discovery and targeting of such immune suppressive programs has had limited success to date, supporting a critical need for identifying signaling pathways that activate these programs. The MUC1-C oncoprotein is aberrantly overexpressed in human carcinomas and is associated with poor clinical outcomes. MUC1-C promotes the epithelial-mesenchymal transition (EMT) and the cancer stem cell (CSC) state. Recent advances have demonstrated that MUC1-C also activates a program of immune evasion in human cancer cells that includes upregulation of PD-L1 expression and the suppression of immune effectors, such as IFN. In addition, targeting MUC1-C has been found to effectively reverse tumor immune evasion. These findings have emphasized the need for developing agents that target MUC1-C for the immunotherapy of human cancers. In this way, selective and potent antibodies generated against the MUC1-C extracellular domain are under development as an antibody-drug conjugate (ADC) and for antibody- dependent cell-mediated cytotoxicity (ADCC). In addition, a peptide inhibitor of the MUC1-C cytoplasmic domain has been developed in a nanoparticle formulation, based on the findings that this agent inhibits PD-L1 expression and activates anti-tumor T cells in the immune microenvironment. The MUC1-C-targeted agents will be studied in genetically-engineered mouse models (GEMMs) for anti-tumor activity, as well as effects on the immune microenvironment when used alone and in combination with PD-1/PD-L1 axis blockade. These studies will be integrated with assessment of MUC1-C expression in human tumors as a metric of the suppressive immune microenvironment. The overall goal will be to develop agents that target MUC1-C and are advanced to clinical evaluation as novel immunotherapeutics.