Mitochondrial Metabolic Reprogramming and Immune Evasion in Colorectal Cancer: Research Advances and Mechanistic Perspectives
- 1The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China
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.
Related
- HER3 mediates metabolic reprogramming in metastatic colorectal and pancreatic cancer
- Mechanistic insights on mogrosides as bifunctional regulators of metabolic reprogramming and immune modulation in tumor microenvironment
- Research advances in amino acid metabolic reprogramming in colorectal cancer liver metastasis
- Hypoxia-inducible factor-1α–mediated metabolic reprogramming in sepsis-associated organ dysfunction: organ-specific metabolic mismatch and therapeutic perspectives
- Mitochondrial metabolic reprogramming by a glutamine antagonist radioenhancer conjugate drives pyroptosis and antitumor immunity
BibTeX
@article{ding2026mitochondrial,
title = {{Mitochondrial Metabolic Reprogramming and Immune Evasion in Colorectal Cancer: Research Advances and Mechanistic Perspectives}},
author = {Da Ding and Jingyi Hu and Yitong Wang and Lei Jiang},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209131},
url = {https://www.mdpi.com/1422-0067/27/20/9131},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mitochondrial Metabolic Reprogramming and Immune Evasion in Colorectal Cancer: Research Advances and Mechanistic Perspectives
AU - Da Ding
AU - Jingyi Hu
AU - Yitong Wang
AU - Lei Jiang
PY - 2026
DA - 2026/10/15
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209131
UR - https://www.mdpi.com/1422-0067/27/20/9131
AB - 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.
SN - 1422-0067
ER -