Department of Surgery II, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
Cancer Immune Therapy Research Center, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
Int J Mol Sci. 2023 Aug 28;24(17):13353. doi: 10.3390/ijms241713353.
The tumor microenvironment (TME) plays a pivotal role in the fate of cancer cells, and tumor-infiltrating immune cells have emerged as key players in shaping this complex milieu. Cancer is one of the leading causes of death in the world. The most common standard treatments for cancer are surgery, radiation therapy, and chemotherapeutic drugs. In the last decade, immunotherapy has had a potential effect on the treatment of cancer patients with poor prognoses. One of the immune therapeutic targeted approaches that shows anticancer efficacy is a type 2 diabetes medication, metformin. Beyond its glycemic control properties, studies have revealed intriguing immunomodulatory properties of metformin. Meanwhile, several studies focus on the impact of metformin on tumor-infiltrating immune cells in various tumor models. In several tumor models, metformin can modulate tumor-infiltrated effector immune cells, CD8, CD4 T cells, and natural killer (NK) cells, as well as suppressor immune cells, T regulatory cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). In this review, we discuss the role of metformin in modulating tumor-infiltrating immune cells in different preclinical models and clinical trials. Both preclinical and clinical studies suggest that metformin holds promise as adjunctive therapy in cancer treatment by modulating the immune response within the tumor microenvironment. Nonetheless, both the tumor type and the combined therapy have an impact on the specific targets of metformin in the TME. Further investigations are warranted to elucidate the precise mechanisms underlying the immunomodulatory effects of metformin and to optimize its clinical application in cancer patients.
肿瘤微环境（TME）在癌细胞的命运中起着关键作用，浸润肿瘤的免疫细胞已成为塑造这种复杂环境的关键因素。癌症是世界上主要的死亡原因之一。癌症最常见的标准治疗方法是手术、放射治疗和化疗药物。在过去的十年中，免疫疗法对预后不良的癌症患者的治疗产生了潜在的影响。具有抗癌疗效的免疫治疗靶向方法之一是一种 2 型糖尿病药物，二甲双胍。除了其血糖控制特性外，研究还揭示了二甲双胍有趣的免疫调节特性。同时，有几项研究关注二甲双胍对各种肿瘤模型中浸润肿瘤的免疫细胞的影响。在几种肿瘤模型中，二甲双胍可以调节肿瘤浸润的效应免疫细胞，如 CD8、CD4 T 细胞和自然杀伤（NK）细胞，以及抑制性免疫细胞，如调节性 T 细胞、肿瘤相关巨噬细胞（TAMs）和髓源性抑制细胞（MDSCs）。在这篇综述中，我们讨论了二甲双胍在调节不同临床前模型和临床试验中浸润肿瘤的免疫细胞中的作用。临床前和临床研究都表明，二甲双胍通过调节肿瘤微环境中的免疫反应，有望成为癌症治疗的辅助疗法。然而，肿瘤类型和联合治疗都对 TME 中二甲双胍的特定靶点有影响。需要进一步的研究来阐明二甲双胍免疫调节作用的精确机制，并优化其在癌症患者中的临床应用。
