ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Metabolic Profiling of the TME Uncovers the Contrasting Impacts of CKMT2 and PDE2A in CRC Progression and Therapeutic Response
Yuxiang Fu 1
Jianbo Lai 1
Kaibin Huang 1
Liping Liu 1
Guixiang Liao 2
1. Shenzhen People's Hospital, Shenzhen, China
2. Shenzhen People's Hospital, Jinan University, Shenzhen, China
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Abstract
Background Colorectal cancer (CRC) remains a major cause of cancer-related morbidity and mortality, with high recurrence rates and limited treatment options for metastatic disease. The tumor microenvironment (TME) and metabolic reprogramming are critical drivers of CRC progression, influencing immune responses, therapeutic resistance, and patient outcomes. Objective This study explores the interplay between metabolic reprogramming and the TME in CRC using transcriptomic data and bioinformatics approaches to identify metabolically and microenvironmentally defined CRC subtypes and candidate biomarkers. Methods Gene expression and clinical data were obtained from TCGA colorectal adenocarcinoma (COAD), rectal adenocarcinoma (READ), and six GEO CRC datasets. Immunohistochemistry (IHC) was performed to validate PDE2A and CKMT2 expression in CRC tissues. Bioinformatic analyses were conducted using R software v4.0.3. Results We identified 220 TME-and 40 metabolism-related differentially expressed genes (DEGs) in CRC. Consensus clustering of these TMET genes revealed two distinct subtypes: Cluster 1 (C1), associated with poorer survival, an immune-mesenchymal phenotype, and frequent mutations in TTN and BRAF, and Cluster 2 (C2), characterized by enriched TP53 and APC mutations, classic tumor suppressor pathway activation, and higher genomic instability. Metabolically, C1 was characterized by lipid metabolism and extracellular matrix remodeling,
Summary
Keywords
Cancer hallmarks, colorectal cancer, metabolic reprogramming, RNA sequencing, Tumor Microenvironment
Received
25 October 2025
Accepted
20 February 2026
Copyright
© 2026 Fu, Lai, Huang, Liu and Liao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Guixiang Liao
Disclaimer
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