Cancers escape normal immune surveillance through several pathways. For example, T cells isolated from tumors have been found to be dysfunctional, opening the door to possible immunotherapy interventions, such as immune-checkpoint inhibitors. However, significant clinical responses to immunotherapy have been observed in only a subset of patients and cancer types. T-cell exhaustion is another variable at play, resulting in reduced efficacy of the immune system in removing cancerous cells. To address these clinical challenges and design predictably effective cancer treatments, we must elucidate the precise underlying regulatory mechanisms that determine tumor-specific T-cell functional states and their potential for therapeutic reprogramming. In this webinar, we review the underlying mechanisms and epigenetic programs determining tumor-specific T-cell dysfunction and reprogrammability and discuss current challenges and outstanding research questions in cancer immunotherapy.