Although checkpoint inhibitors targeting PD-1/PD-L1 and/or CTLA-4 T cell coinhibitory receptors have revolutionized cancer treatment and rejuvenated the field of immuno-oncology, immunostimulatory agonist mAbs targeting costimulatory receptors, including members of the TNF receptor superfamily (TNFRSF) such as 4-1BB (CD137), have gained great momentum in clinical development for cancer immunotherapy beyond their successful application in chimeric antigen receptor (CAR) T cell therapy (1–3). The gene discussed is TNFRSF9; the disease is cancer.