γδ T 细胞具有检测多种肿瘤且突变负荷低的独特能力，使其成为 CAR-T 细胞疗法的有吸引力的候选者。与αβ T细胞和其他免疫细胞不同，γδ T细胞在MHC非限制性、选择性细胞募集和快速激活方面具有优越性。然而，临床试验显示的临床获益有限，γδT细胞的过继移植往往达不到预期。我们假设 γδ T 细胞在根除肿瘤细胞方面的有限效力可能归因于抑制性 PD-1/PD-L1 轴诱导的抑制性肿瘤微环境。在此，我们构建了能够分泌人源化抗PD-1抗体的新型装甲γδT细胞，称为“Lv-PD1-γδT细胞”。Lv-PD1-γδT细胞表现出更好的增殖能力和增强的针对肿瘤细胞的细胞毒性，从而增强了卵巢肿瘤小鼠的治疗效果和生存益处。这些工程细胞表现出超过 29 天的体内存活时间，并且在免疫缺陷的 NOD/SCID/γ 缺失小鼠中没有任何致瘤性的潜力。我们还发现 Lv- PD1-γδ T 细胞在人源化 NOD/SCID/γ 缺失小鼠中表现出优异的耐受性和安全性，通过在肿瘤中局部分泌抗 PD1 抗体来减弱或消除免疫抑制并最大化细胞毒性功效，Lv-PD1-γδ T 细胞可以发挥作用作为一种有前景的“现成”癌症细胞疗法。© 2023。四川大学华西医院。

γδ T cells have the unique ability to detect a wide range of tumors with low mutation burdens, making them attractive candidates for CAR-T-cell therapy. Unlike αβ T cells and other immune cells, γδ T cells are superior in MHC non-restriction, selective cell recruitment, and rapid activation. However, clinical trials have shown limited clinical benefits, and the adoptive transplantation of γδ T cells has often fallen short of expectations. We hypothesized that the limited effectiveness of γδ T cells in eradicating tumor cells may be attributed to the inhibitory tumor microenvironment induced by the suppressive PD-1/PD-L1 axis. Herein, we constructed novel armored γδ T cells capable of secreting humanized anti-PD-1 antibodies, referred to as "Lv-PD1-γδ T cells. Lv-PD1-γδ T cells showed improved proliferation and enhanced cytotoxicity against tumor cells, resulting in augmented therapeutic effects and survival benefits in ovarian tumor-bearing mice. These engineered cells demonstrated a prolonged in vivo survival of more than 29 days, without any potential for tumorigenicity in immunodeficient NOD/SCID/γ null mice. We also found that Lv-PD1-γδ T cells exhibited excellent tolerance and safety in humanized NOD/SCID/γ null mice. With attenuated or eliminated immunosuppression and maximized cytotoxicity efficacy by the local secretion of anti-PD1 antibodies in tumors, Lv-PD1-γδ T cells can serve as a promising "off-the-shelf" cell therapy against cancers.© 2023. West China Hospital, Sichuan University.