Metabolic crossroads: unravelling immune cell dynamics in gastrointestinal cancer drug resistance

Abstract

Metabolic reprogramming within the tumor microenvironment (TME) plays a critical role in driving drug resistance in gastrointestinal cancers (GI), particularly through the pathways of fatty acid oxidation and glycolysis. Cancer cells often rewire their metabolism to sustain growth and reshape the TME, creating conditions such as nutrient depletion, hypoxia, and acidity that impair antitumor immune responses. Immune cells within the TME also undergo metabolic alterations, frequently adopting immunosuppressive phenotypes that promote tumor progression and reduce the efficacy of therapies. The competition for essential nutrients, particularly glucose, between cancer and immune cells compromises the antitumor functions of effector immune cells, such as T cells. Additionally, metabolic by-products like lactate and kynurenine further suppress immune activity and promote immunosuppressive populations, including regulatory T cells and M2 macrophages. Targeting metabolic pathways such as fatty acid oxidation and glycolysis presents new opportunities to overcome drug resistance and improve therapeutic outcomes in GI cancers. Modulating these key pathways has the potential to reinvigorate exhausted immune cells, shift immunosuppressive cells toward antitumor phenotypes, and enhance the effectiveness of immunotherapies and other treatments. Future strategies will require continued research into TME metabolism, the development of novel metabolic inhibitors, and clinical trials evaluating combination therapies. Identifying and validating metabolic biomarkers will also be crucial for patient stratification and treatment monitoring. Insights into metabolic reprogramming in GI cancers may have broader implications across multiple cancer types, offering new avenues for improving cancer treatment.

Keywords: Gastrointestinal cancers; drug resistance; immune cells; metabolic pathways; tumor microenvironment.

Figure 1

Fatty acid oxidation metabolic pathways in immune cells contributing to drug resistance in GI cancers. GI: Gastrointestinal cancers; ACC: Acetyl-CoA carboxylase; FASN: fatty acid synthase.

Figure 2

Glycolysis pathways in immune cells and their role in mediating drug resistance in GI cancers. This figure illustrates the critical metabolic pathways in MDSCs, TAMs, and Tregs that contribute to drug resistance in gastrointestinal cancers. These immune cells undergo metabolic reprogramming, promoting an immunosuppressive TME that supports cancer progression and reduces the efficacy of therapies. MDSCs: Myeloid-derived suppressor cells; TAMs: tumor-associated macrophages; Tregs: regulatory T cells; TME: tumor microenvironment.