In this study, we sought to characterize the effects of repeated doses and long-term use of agonistic anti-4-1BB mAbs in cancer immunotherapy to reflect the observations in a clinical setting.24,25 We provide evidence that chronic 4-1BB triggering leads to excessive LN swelling along with granuloma formation in TDLNs and describe the cellular mechanism associated with granuloma formation and its impacts on anti-4-1BB therapy. The gene discussed is TNFRSF9; the disease is Granuloma.