T 细胞重定向疗法改变了血液疾病的治疗格局。 T 细胞依赖性双特异性抗体 (TDB) 作为条件激动剂，诱导多克隆 T 细胞反应，导致靶细胞破坏和细胞因子释放。这种反应与其对周围先天免疫群体的影响之间的关系尚未得到充分探索。在这里，我们展示了莫苏奈妥珠单抗治疗患者会导致外周血中自然杀伤 (NK) 细胞激活。我们在体外模拟了这种现象，发现TDB介导的杀伤激活了NK细胞，增加了自然杀伤功能和抗体依赖性细胞毒性（ADCC），并增强了巨噬细胞执行抗体依赖性细胞吞噬作用（ADCP）的能力。这种增强是由 TDB 治疗释放的细胞因子触发的，其中 IL2 和 IFNγ 分别是 ADCC 和 ADCP 增加的主要驱动因素。令人惊讶的是，通过中和 NK 细胞的 IL10 和巨噬细胞的 TNFα，可以进一步增强细胞溶解能力。最后，我们证明 TDB 治疗增强了 Fc 驱动的体内正交实体瘤靶标的杀伤功效。这些结果为利用适应性和先天免疫反应的新型抗体治疗组合提供了理论基础。

T cell-retargeting therapies have transformed the therapeutic landscape for hematological diseases. T cell-dependent bispecific antibodies (TDBs) function as conditional agonists that induce a polyclonal T-cell response, resulting in target cell destruction and cytokine release. The relationship between this response and its effects on surrounding innate immune populations has not been fully explored. Here we show that treatment with mosunetuzumab in patients results in natural killer (NK) cell activation in the peripheral blood. We modeled this phenomenon in vitro and found that TDB-mediated killing activated NK cells, increasing natural killing function and antibody-dependent cellular cytotoxicity (ADCC), and enhanced the capability of macrophages to perform antibody-dependent cellular phagocytosis (ADCP). This enhancement was triggered by cytokines released through TDB treatment, with IL2 and IFNγ being major drivers for increased ADCC and ADCP, respectively. Surprisingly, cytolytic ability could be further augmented through neutralization of IL10 for NK cells and TNFα for macrophages. Finally, we showed that TDB treatment enhanced the efficacy of Fc-driven killing to an orthogonal solid tumor target in vivo. These results provide rationale for novel antibody therapy combinations that take advantage of both adaptive and innate immune responses.