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CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications. [Display omitted] • T cell-specific deletion of CD137 limits the presence of CD8+ Tex cells in tumors • NF-κB-dependent CD137 signaling stimulates Tex cell proliferation and differentiation • CD137 activation drives the Tox-dependent epigenetic remodeling of Tex cell genes • Anti-PD1 efficacy is improved by subsequent CD137 stimulation Manipulating exhausted T (Tex) cells has therapeutic implications. Pichler et al. found that the activating receptor, CD137 (4-1BB), was specifically expressed by Tex cells. CD137 signaling promoted TCR-independent proliferation and terminal differentiation of Tex cells. In murine tumor models, treatment with CD137 agonists specifically after anti-PD1 therapy improves anti-tumor responses. [ABSTRACT FROM AUTHOR]