Immune checkpoint inhibitors have revolutionized the treatment landscape for a number of cancers over the last few decades. Nevertheless, a majority of patients still do not benefit from these treatments. Such patient-specific lack of response can be predicted, in part, from the immune phenotypes present in the tumor microenvironment. We provide a perspective on options to reprogram the tumors and their microenvironment to increase the therapeutic efficacy of immunotherapies and expand their efficacy against cold tumors. Additionally, we review data from current preclinical and clinical trials aimed at testing the different therapeutic options in monotherapy or preferably in combination with checkpoint inhibitors.