肿瘤细胞治疗研究
英文原题：Metformin sensitizes esophageal squamous cell carcinoma to Vγ9Vδ2 T cell-mediated cytotoxicity by upregulating BTN3A1 and BTN2A1.
二甲双胍是一种一线抗糖尿病药物，具有广谱抗肿瘤特性，但其潜在的免疫调节机制尚未完全阐明。
二甲双胍作为一线抗糖尿病药物，具有广谱抗肿瘤特性，但其潜在的免疫调节机制尚未完全阐明。在此，我们证明二甲双胍以 AMPK 依赖的方式显著上调食管癌细胞上 BTN3A1 和 BTN2A1 的表达，从而使其对 Vγ9Vδ2 T 细胞介导的细胞毒性敏感。这种分子致敏增强了肿瘤免疫原性，导致体外协同性肿瘤细胞杀伤以及异种移植模型中肿瘤生长的有效抑制。在机制上，二甲双胍诱导的 BTN3A1/BTN2A1 上调促进了 Vγ9Vδ2 T 细胞活化以及肿瘤组织中 Granzyme B 介导的细胞凋亡。联合治疗表现出极好的耐受性，未观察到全身毒性。此外，整合 GEPIA3 数据库和临床标本分析，我们发现 BTN3A1 和 BTN2A1 在食管癌组织中高表达但具有异质性，并且二甲双胍介导的上调可能恢复对 Vγ9Vδ2 T 细胞免疫治疗的敏感性，尤其是在基线表达较低的患者中——揭示了二甲双胍一种新的免疫调节功能，为其重新定位为针对食管癌等免疫冷肿瘤的联合用药提供了有力依据。
Metformin, a first-line anti-diabetic agent, exhibits broad-spectrum antitumor properties, though its underlying immunomodulatory mechanisms remain incompletely characterized. Here, we demonstrate that metformin significantly upregulates BTN3A1 and BTN2A1 expression on esophageal cancer cells in an AMPK-dependent manner, thereby sensitizing them to Vγ9Vδ2 T cell-mediated cytotoxicity. This molecular priming enhanced tumor immunogenicity, leading to synergistic tumor cell killing in vitro and potent suppression of tumor growth in xenograft models. Mechanistically, metformin-induced BTN3A1/BTN2A1 upregulation promoted Vγ9Vδ2 T cell activation, and Granzyme B-mediated apoptosis in tumor tissues. The combination therapy demonstrated excellent tolerability without observable systemic toxicity. Moreover, Integrating GEPIA3 database and clinical specimen analyses, we find that BTN3A1 and BTN2A1 are highly but heterogeneously expressed in esophageal cancer tissues, and that metformin‑mediated upregulation may restore sensitivity to Vγ9Vδ2 T cell immunotherapy particularly in patients with low baseline expression-uncovering a novel immunomodulatory function of metformin that provides a compelling rationale for its repurposing as a combinatorial agent against immunologically cold tumors such as esophageal carcinoma.
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