Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities
- 1Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
- 2School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
Abstract
Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide. Metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome are associated with CRC risk. Metabolic abnormalities may contribute to colorectal tumorigenesis and reshape the tumor immune microenvironment, which in turn influence immune dysfunction and therapeutic resistance. Exhausted CD8+ T cells exhibit impaired effector function, sustained inhibitory receptor expression, and transcriptional and epigenetic reprogramming. Metabolic stressors within the CRC microenvironment may modulate T-cell function and exhaustion-associated states. Additionally, other immune populations (natural killer cells, macrophages, myeloid-derived suppressor cells, dendritic cells, and regulatory T cells) may develop distinct dysfunctional or immunosuppressive states. Recent single-cell and spatial studies have indicated the heterogeneity of these immunometabolic interactions in CRC. This review examines the interactions of the systemic and tumor-associated metabolic alterations with T-cell exhaustion and other forms of immune dysfunction in CRC. We discuss the influence of glucose, lipid, amino acid, and mitochondrial metabolism, hypoxia, microbiota-derived metabolites, and chronic inflammation in shaping tumor–immune interactions. Finally, we reviewed therapeutic strategies targeting immunometabolic pathways and their potential integration with immune checkpoint blockade. Overall, understanding these interactions may help identify immunometabolic vulnerabilities for informing precise therapeutic strategies for CRC.
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BibTeX
@article{jeon2026metabolic,
title = {{Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities}},
author = {Jieun Jeon and Hye Suk Baek and Kibeom Park and Mee-Na Park and Na Hyeon Heo and Sohyeon Cheon and Gahyeon Kim and Shin Kim},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209134},
url = {https://www.mdpi.com/1422-0067/27/20/9134},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Metabolic Dysfunction and T-Cell Exhaustion in Colorectal Cancer: Mechanisms, Microenvironment Remodeling, and Therapeutic Opportunities
AU - Jieun Jeon
AU - Hye Suk Baek
AU - Kibeom Park
AU - Mee-Na Park
AU - Na Hyeon Heo
AU - Sohyeon Cheon
AU - Gahyeon Kim
AU - Shin Kim
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209134
UR - https://www.mdpi.com/1422-0067/27/20/9134
AB - Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality worldwide. Metabolic disorders such as obesity, diabetes mellitus, dyslipidemia, and metabolic syndrome are associated with CRC risk. Metabolic abnormalities may contribute to colorectal tumorigenesis and reshape the tumor immune microenvironment, which in turn influence immune dysfunction and therapeutic resistance. Exhausted CD8+ T cells exhibit impaired effector function, sustained inhibitory receptor expression, and transcriptional and epigenetic reprogramming. Metabolic stressors within the CRC microenvironment may modulate T-cell function and exhaustion-associated states. Additionally, other immune populations (natural killer cells, macrophages, myeloid-derived suppressor cells, dendritic cells, and regulatory T cells) may develop distinct dysfunctional or immunosuppressive states. Recent single-cell and spatial studies have indicated the heterogeneity of these immunometabolic interactions in CRC. This review examines the interactions of the systemic and tumor-associated metabolic alterations with T-cell exhaustion and other forms of immune dysfunction in CRC. We discuss the influence of glucose, lipid, amino acid, and mitochondrial metabolism, hypoxia, microbiota-derived metabolites, and chronic inflammation in shaping tumor–immune interactions. Finally, we reviewed therapeutic strategies targeting immunometabolic pathways and their potential integration with immune checkpoint blockade. Overall, understanding these interactions may help identify immunometabolic vulnerabilities for informing precise therapeutic strategies for CRC.
SN - 1422-0067
ER -