基于 T 细胞的癌症免疫疗法通常依赖于膜结合的细胞毒性增强剂，例如自体 αβ T 细胞中表达的嵌合抗原受体。这些方法受到合成结构的强直信号和与制造相关的成本的限制。 γδ T 细胞是一种新兴的细胞治疗替代品，具有先天的抗肿瘤活性、有效的抗体依赖性细胞毒性和最小的同种异体反应性。我们提出了一种围绕 Vγ9Vδ2 T 细胞的先天特性构建的免疫治疗平台技术，利用这种细胞类型的特定特征并提供一种可招募旁观者免疫力的同种相容细胞疗法。我们对 γδ T 细胞进行了改造，使其以 scFv-Fc 融合蛋白和促有丝分裂 IL-15Rα-IL-15 融合蛋白 (stIL15) 的形式分泌合成的肿瘤靶向调理素。使用GD2作为模型抗原，我们发现GD2特异性分泌调理素的Vγ9Vδ2 T细胞（stIL15-OPS-γδ T细胞）具有增强的细胞毒性并促进其他淋巴和骨髓细胞的旁观者活性。 stIL-15 的分泌消除了补充外源细胞因子的需要，并进一步介导旁观者自然杀伤细胞的激活。与未修饰的 γδ T 细胞相比，stIL15-OPS-γδ T 细胞表现出优异的体内皮下肿瘤控制能力和血液持久性。此外，stIL15-OPS-γδ T 细胞在动物模型和体外对患者来源的骨肉瘤有效，添加唑来膦酸可以增强疗效。总之，这些数据确定 stIL15-OPS-γδ T 细胞作为候选同种异体细胞治疗平台，将直接细胞溶解与旁观者激活相结合，以促进肿瘤控制。

T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control.