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.

Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS‐010759

“…In the context of cancer, most studies report an inhibitory role of metformin on M2 macrophages (pro‐tumorigenic; reviewed in [ 46 , 58 ]). However, in conditions such as obesity [ 59 , 60 ], atherosclerosis [ 61 ], and bone‐associated pathologies [ 62 ] metformin induces M2 polarization.…”

Apoptosis, a Metabolic “Head-to-Head” between Tumor and T Cells: Implications for Immunotherapy

“…Besides its described protective effects against T-cell apoptosis, metformin also enhances the migration of adoptively transferred antigen-specific CD8 + T cells into tumor sites while preserving T-cell multifunctionality, a mechanism reliant on AMPK activation [ 236 ].…”

Metabolic vulnerability of cancer stem cells and their niche

“…Several studies suggest that the effects of pharmacological agents inhibiting mitochondrial metabolism, well reported for bulk tumor cells and cancer stem cells, extend beyond tumor cells and apply also to TAMs, which can contribute to their efficacy. Metformin has the potential to shift the balance of TAMs from an immunosuppressive M2 phenotype to an antitumor M1 phenotype ( Wu et al, 2022 ; Abdelmoneim et al, 2023 ). A plethora of studies on different cancer models report its efficacy against TAMs ( Liu et al, 2018 ; Wang et al, 2020 ; Munoz et al, 2021 ; Wei et al, 2021 ; Kang et al, 2022 ; Taylor et al, 2022 ; Cao et al, 2023 ).…”