Immunotherapies such as PD-1 blockade have revolutionized cancer care. Yet most patients do not experience sustained (durable) benefit from blockade of T cell inhibitory receptors. Unfortunately, current biomarkers do not adequately predict patient response or resistance to immunotherapy; and successful strategies to overcome immunotherapy resistance have been lacking. Both gaps reflect our incomplete understanding of how durable immunity carried out by T cells is achieved. Progenitor T cells normally balance the mutually opposing demands of differentiation and self- renewal by transmitting unequal anabolic activating signals to daughter cells. In the setting of cancer, however, sustained T cell activation skews the normal regenerative equilibrium of balanced differentiation and renewal towards progressive dysfunction of differentiated cells along with progressive loss of self-renewing T cells. It was previously presumed that PD-1 blockade acted by restoring potency to the most dysfunctional T cells. Instead, emerging consensus has demonstrated that PD-1 blockade can only function by inducing greater division and differentiation of self- renewing T cells, which are already in peril. This preclinical and translational application marshals our basic discoveries concerning the signaling and cell biology of T cell regeneration to tackle a major clinical roadblock in cancer care. Performing the aims of this proposal will enable determination of 1) whether anti-cancer immunity and immunotherapy impact the self-renewal of CD8+ T cells; 2) whether immunotherapy can be improved by augmenting CD8+ T cell self-renewal; and 3) whether patient response and resistance to immune checkpoint blockade can be predicted from the abundance of self-renewing T cells. This proposal would address two critical unmet patient needs: a non-invasive predictive biomarker for response and resistance to immunotherapy across cancer types; and a novel strategy for resistance-directed treatment enabling immunotherapy to benefit the majority, rather than the minority of patients.