Using diverse preclinical tumor models of prostate and bladder cancer, including an autochthonous prostate tumor (Pten−/−/trp53−/−) that respond poorly to radiation therapy (RT) and anti-PD-L1 combinations, the key drivers of this resistance within the TME were profiled and used to develop rationalized combination therapies that simultaneously enhance activation of anti-cancer T cell responses and reprogram the immunosuppressive TME. This evidence concerns the gene CD274 and urinary bladder carcinoma.