Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.

Abstract

Metabolic reprogramming within the tumor microenvironment (TME) is a pivotal driver of CD8⁺ T cell dysfunction in cancer. Tumor cells outcompete T cells for essential nutrients, including glucose and amino acids, while accumulating immunosuppressive metabolites such as lactate and 2-hydroxyglutarate. Beyond direct functional impairment, emerging research reveals that these metabolic alterations orchestrate CD8⁺ T cell transcriptional programs by remodeling their epigenome-via histone modifications, DNA methylation, and non-coding RNA networks-thereby dictating their differentiation, cytotoxic potential, and memory formation. A deeper understanding of how TME-derived metabolic signals shape the epigenetic landscape of CD8⁺ T cells is crucial for improving current cancer immunotherapeutic strategies. This review systematically delineates how key TME metabolic features, including nutrient deprivation and oncometabolite accumulation, regulate CD8⁺ T cell fate through epigenetic pathways. Furthermore, we discuss promising therapeutic strategies that target the metabolism-epigenetics axis to reinvigorate CD8⁺ T cell anti-tumor immunity, offering novel perspectives for enhancing adoptive cell therapy and immune checkpoint blockade.