Background: The CD30/CD16A bispecific tetravalent TandAb antibody AFM13 recruits and activates NK cells by specific binding to CD16A for targeted lysis of CD30⁺ tumor cells. Given promising clinical activity and safety profile of AFM13 and proof-of-mechanism demonstrating dependence on the immune response, potential synergy of AFM13 and checkpoint inhibitors was evaluated. Methods: Efficacy was assessed by in vitro cytotoxicity with human PBMCs, enriched NKs, and CD30⁺ target cells as well as cell line and patient-derived xenograft in vivo models with AFM13, anti-CTLA-4, anti-PD-1, or anti-CD137 antibodies. Results: AFM13 demonstrated higher potency and efficacy toward target and effector cells relative to other CD30⁺ antibody formats (EC50 = 15pM). These favorable properties resulted in superior cytotoxicity when AFM13 was incubated with CD30⁺ tumor cells and enriched NK cells. Single treatment with AFM13 at suboptimal concentrations (1 pM) induced effector-to-target cell-dependent lysis of CD30⁺ lymphoma cells up to 40% using enriched NK cells. Immune-modulating antibodies alone mediated substantially lower lysis ( < 25%). However, the addition of anti-PD-1 or anti-CD137 to AFM13 strongly enhanced specific lysis up to 70%, whereas the addition of anti-CTLA-4 to AFM13 showed no beneficial effect. The most impressive increase of efficacy was observed when AFM13 was applied together with a combination of anti-PD-1 and anti-CD137. In vivo, synergy of AFM13 and CPI combination was observed with each CPI tested and augmented with anti-PD1 (regression in 9/10 tumors), ant-CTLA-4 (3/10), and anti-CD137 mAb (3/10) and influenced by presence of regulatory T cells, NK cells, and Th1 cytokines. Conclusions: Our findings support engagement of NK cells using CD30/CD16A TandAbs by binding to CD16A does not completely exploit the efficacy of NK cells. Therefore combination trials performed with companion intratumoral assessment may personalize dual-Ab therapy and augment the efficacy of AFM13 and CPIs.