biostudies-literaturePichler ACIntramural NIH HHS1631-1648.e10https://www.ebi.ac.uk/biostudies/studies/S-EPMC10649891biostudies-literatureUnknown56(7)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 inImmunityTCR-independent CD137 (4-1BB) signaling promotes CD8<sup>+</sup>-exhausted T cell proliferation and terminal differentiation.PMC10649891ZIA AI001240Lucca LEJoffre OSalomon BLBlanquart ELemaitre LTosolini MEkren RGuillerey CVoisin ACarrie NGolec DPAxisa PPWatts THCannons JLGrinberg-Bleyer Ydo Souto LPichler ACSchwartzberg PLAvet-Loiseau HCuisinier MJoubert MVGhazali SMazzotti CMaheo SFeliu VMartinet LfalseTCR-independent CD137 (4-1BB) signaling promotes CD8<sup>+</sup>-exhausted T cell proliferation and terminal differentiation.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 in2023-01-01T00:00:00Z2023 Jul2026-05-29T10:23:41.902Z2025-04-06T01:19:09.528ZS-EPMC106498913739273710.1016/j.immuni.2023.06.007