Bispecific antibodies pairing a shared 4-1BB epitope with non-overlapping HER2 epitopes drove HER2-dependent 4-1BB clustering, amplifying T-cell activation and tumor growth inhibition. In vivo, this pairing enhanced antitumor efficacy and tumor infiltration, while reducing systemic inflammation compared to urelumab - establishing a generalizable strategy for TNFRSF-targeted immunotherapy.