γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.

γδ T 细胞在应激监测以及感染和癌变免疫中发挥着独特的重要作用。人类 γδ T 细胞能够独立于人类白细胞抗原 (HLA) 限制识别并杀死转化细胞，这是传统 αβ T 细胞的基本特征。Vγ9Vδ2 γδ T 细胞普遍存在于健康成人的外周血中，通过依赖于嗜丁酸蛋白分子的机制被微生物或内源性肿瘤衍生的焦磷酸盐激活。表达其他 T 细胞受体可变基因（尤其是 Vδ1）的 γδ T 细胞在粘膜组织中更为丰富。除了 T 细胞受体外，γδ T 细胞通常还表达激活的自然杀伤 (NK) 受体，例如 NKp30、NKp44 或 NKG2D，它们与应激诱导的表面分子结合，这些分子在健康细胞上不存在，但在恶性细胞上经常表达。因此，γδT细胞被赋予至少两个独立的识别系统来感知肿瘤细胞并启动抗癌效应机制，包括细胞因子的产生和细胞毒性。鉴于其不依赖于 HLA 的有效抗肿瘤活性，人们越来越有兴趣将 γδ T 细胞的独特潜力转化为创新的细胞癌症免疫疗法。在这里，我们讨论增强基于 γδ T 细胞的免疫疗法疗效的最新进展。这包括 γδ T 细胞的体内激活和肿瘤靶向策略、体外扩增方案的优化以及基因修饰的 γδ T 细胞的开发。同样重要的是考虑与其他治疗策略的潜在协同作用，特别是检查点抑制剂、化疗或先天免疫的（局部）激活。