CD137 in cancer therapy - bench to bedside

CD137 (4-1BB; TNFRSF9) is an inducible costimulatory receptor of the tumor necrosis factor receptor (TNFR) superfamily expressed on activated CD8⁺ and CD4⁺ T-cells, natural killer cells, and dendritic cells. By reinforcing T-cell survival, expansion, and memory formation, CD137 has become an attractive target in cancer immunotherapy. Therapeutic strategies include agonistic monoclonal antibodies, bispecific molecules, and adoptive cell therapies enriched for tumor-reactive lymphocytes. Clinical-grade closed bioreactor systems feature a CD137-based enrichment platform utilizing antigen-induced CD137 upregulation to isolate and expand clinically relevant T-cell subsets. Additional innovations such as dendritic cell co-culture systems expressing CD137L and single-cell technologies that characterize highly reactive CD137⁺ T-cells further enhance precision and potency. Clinical trials of CD137 agonists have shown promising anti-tumor activity; however, hepatotoxicity and variable patient responses remain challenges. Recent work in non-human primate models has clarified the role of CD137 signaling in modulating alloreactivity, with implications for graft-versus-host disease. Despite ongoing barriers - including toxicity, therapeutic resistance, and limited biomarkers - CD137 remains a compelling immunologic target. Future efforts will emphasize context-specific agonism, refined cellular engineering, and multi-omic integration to improve patient selection and therapeutic design. This review summarizes CD137 biology, emerging therapeutic strategies, and translational and clinical directions.