Described herein are methods and compostions relating to breaking or inhibiting T cell exhaustion by increasing TMEM16F levels and/or activity. The methods and compositions can thereby further relate to treatment of viral infections or cancer, treatment of a chronic disease, vaccine administration, administering a CAR-T therapy, or increasing the number of T-bet+ T cells in a subject. In some embodiments, the methods relate to treatment of an autoimmune or inflammatory disease by inhibiting TMEM16F levels and/or activity.
