Tumor microenvironment and metabolic reprogramming: Unraveling the complex interplay in gastrointestinal tumor liver...

Gastrointestinal tumors (GITs) are among the most prevalent and lethal malignancies worldwide, with liver metastasis (LM) being a major contributor to poor patient prognosis, contributing to recurrence in a substantial proportion (approximately 37 %) of patients undergoing radical gastrectomy. Dismally, the prognosis for GI-LM (Gastrointestinal tumors Liver Metastasis) patients remains exceedingly poor, with survival rates beyond five years languishing below 10 %. Recent studies have highlighted the critical role of tumor metabolic reprogramming and its interaction with the tumor microenvironment (TME) in the progression of gastrointestinal tumor liver metastasis. Tumor cells undergo metabolic alterations, such as enhanced glycolysis, increased glutamine metabolism, and altered lipid metabolism, to meet the demands of rapid proliferation. These metabolic changes also reshape the liver microenvironment by secreting metabolites (e.g., lactate, succinate), promoting immune suppression, angiogenesis, and stromal remodeling, thereby facilitating liver metastasis. Conversely, the liver microenvironment, including immune cells, stromal cells, and extracellular matrix components, influences tumor cell metabolism through nutrient competition, cytokine signaling, and hypoxia-driven mechanisms, creating a bidirectional interaction. This review summarizes the molecular mechanisms underlying the interplay between tumor metabolic reprogramming and the microenvironment in gastrointestinal tumor liver metastasis, explores how metabolic changes drive TME remodeling to promote metastasis, and discusses emerging therapeutic strategies targeting these mechanisms. The aim is to provide new insights for precision medicine in treating gastrointestinal tumor liver metastasis.