Deciphering the Anti-Tumor Mechanisms of Metformin Through Reprogramming of the Tumor Microenvironment

Metformin is a cornerstone medication for type 2 diabetes and exhibits anti-tumor activities. Previous studies have demonstrated that metformin suppresses tumor progression by regulating multiple signaling pathways, including the AMPK, PI3K/AKT/mTOR, and JNK pathways. However, most previous studies have focused on its direct effects on tumor cells, with limited attention to its effects in the TME. The TME constitutes a multifaceted ecosystem that drives tumor development and therapeutic resistance via physical barrier formation, immune evasion, and abnormal angiogenesis. In this review, we systematically summarize the impact and underlying regulatory mechanisms of metformin on distinct components of the TME. In addition, we discuss the individual and combined roles of metformin in immunity and inflammation, as well as vascular, matrix, and metabolic regulation. By elucidating the mechanisms of metformin-mediated TME reprogramming, we aim to provide new perspectives for understanding its anti-tumor effects and facilitating its clinical translation in cancer therapy.