The Impact of Metformin on Tumor-Infiltrated Immune Cells: Preclinical and Clinical Studies

Abstract

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.

Keywords: metformin; tumor microenvironment; tumor-infiltrating lymphocytes.

Figure 1

Effect of Metformin on tumor-infiltrated immune cells. Metformin can target several pathways in CD8+, NK cells, T regulatory cells, MDSCs, and TAMs in the tumor microenvironment in AMPK-dependent and AMPK-independent manners. AMPK: adenosine monophosphate-activated protein kinase; FOXO3: forkhead box O3; c-Myc: cellular Myc; STAT: signal transducer and activator of transcription; PD-L1: programmed death-ligand 1; PD-1: programmed cell death protein 1; NRF2 nuclear factor erythroid 2-related factor 2; mTORC1: mammalian target of rapamycin complex 1; GLUT-1: glucose transporter 1; IFNγ: interferon gama; CXCL1: C-X-C motif chemokine ligand 1; NK; natural killer; PS6: phosphorylation of S6 ribosomal protein; TH17: T helper 17; SIRT1: Situnin 1; Rorc: retinoic acid receptor-related orphan receptor; FOXP3: forkhead box P3; HIF-1: hypoxia-inducible factor-1; MDSCs: myeloid-derived suppressor cells; DACH1: dachshund family transcription factor 1; NF- κB: nuclear factor kappa B; TAMs: tumor-associated macrophages; ROS: reactive oxygen species.