Mitochondrial Metabolic Reprogramming and Immune Evasion in Colorectal Cancer: Research Advances and Mechanistic Perspectives

Abstract

Colorectal cancer (CRC) is one of the most prevalent malignancies of the gastrointestinal tract worldwide. Notably, most patients with microsatellite-stable (MSS) tumors show primary resistance to immune checkpoint inhibitors (ICIs), creating an unmet clinical need. The mechanisms underlying immune evasion and strategies to overcome therapeutic resistance have therefore become important topics in CRC immunology research. Recent studies indicate that mitochondrial metabolic reprogramming contributes to immune evasion in CRC. Tumor cells display metabolic plasticity through dynamic shifts between glycolysis and oxidative phosphorylation (OXPHOS), which can intensify the depletion of critical nutrients, particularly glucose and glutamine, within the tumor microenvironment (TME). These metabolic changes can also promote the accumulation of immunosuppressive metabolites, including lactate, thereby impairing the function of effector cells such as CD8+ T cells and dendritic cells (DCs) and supporting the expansion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Lactate may further reshape the immune landscape through hydroxycarboxylic acid receptor 1 (HCAR1) signaling and histone lactylation. In parallel, mitochondrial quality control can regulate tumor immunogenicity by influencing mtDNA availability and cGAS-STING signaling. Therapeutic approaches targeting glycolysis, glutamine metabolism, fatty acid oxidation, lactate transport, and mitochondrial dynamics have shown immune-sensitizing activity in preclinical models. Nanodelivery systems and gene-editing technologies may improve the spatial and cellular specificity of these interventions. This review summarizes how mitochondrial metabolic reprogramming contributes to immune evasion in CRC and evaluates mitochondria-directed strategies for improving treatment responsiveness, particularly in MSS CRC.