Folate metabolism-associated CYP26A1 is a clinico-immune target in colorectal cancer

Sep 23, 2026

Uploaded by Stanley

Folic acid influences cellular regulation and metabolism, yet its roles in colorectal cancer (CRC)—especially within metabolic pathways and immune evasion—remain insufficiently characterized. A machine-learning FMRG_score was developed from TCGA and GEO cohorts, stratifying CRC patients by modification patterns tied to clinical outcomes and immune features, with reliability verified across external immunotherapy sets. FMRG features were linked to clinical traits, mutations, functions, immune infiltration, therapy response, and drug sensitivity. In vitro and in vivo integration supported a nine-gene folate metabolism risk model, highlighting CYP26A1 as a tumor-promoting and immunosuppressive oncogenic factor.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Colorectal cancer burden and molecular pathways

Immune checkpoint inhibitor therapy and response variability

[www.nature.com/gene](www.nature.com/gene Genes & Immunity)[ Genes & Immunity](www.nature.com/gene Genes & Immunity) ARTICLE OPEN Folate metabolism-associated CYP26A1 is a clinico-immune target in colorectal cancer Yifei Zhu1,2,3,4,9, Teng Zhou1,5,9, Yao Zheng6, Yanxi Yao1,2,3,4, Mingxi Lin1,5, Cheng Zeng 1,5, Yuxin Yan1,5, Yifei Zhou7, Dou-Dou Li8 ✉ and Jian Zhang 1,5 ✉ © The Author(s) 2025, modiﬁed publication 2025 | | Folic acid plays a crucial role in cellular regulation and metabolism, commonly included in dietary supplements. Despite this, its involvement in colorectal cancer (CRC), particularly in metabolic pathways and immune evasion, remains poorly understood. We developed the FMRG_score system using machine learning algorithms on TCGA and GEO data to assess modiﬁcation patterns inﬂuencing clinical outcomes and immune characteristics in CRC. The system’s reliability was validated across multiple external immunotherapy cohorts. We examined associations between FMRG-related features and clinical traits, mutation proﬁles, biological functions, immune inﬁltration, therapy responses, and drug sensitivities. By integrating in vitro and in vivo experiments with bioinformatics, we built a nine-gene risk model linked to folate metabolism for CRC prognosis. Notably, CYP26A1, a key gene in the model, was upregulated in CRC tissues, promoting cell proliferation, migration, invasion, and contributing to an immunosuppressive tumor microenvironment. Signiﬁcant differences in clinical traits, immune inﬁltration, checkpoint expression, therapy response, and drug sensitivity were observed between risk groups. This folate-based scoring system provides a novel tool for evaluating CRC prognosis, tumor microenvironment, and response to immunotherapy. We also propose CYP26A1 as a potential | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | oncogene in CRC, offering new therapeutic insights. | | | | | Genes & Immunity (2025) 26:376–393; [https://doi.org/10.1038/s41435-025-00342-6](https://doi.org/10.1038/s41435-025-00342-6) | | | | | | INTRODUCTION CRC is the third most common malignancy. It is also the second deadliest cancer worldwide [1] . CRC is 1 .5 times more common in men than in women, with most cases occurring after the age of 50 [2] . However, CRC incidence has been increasing in countries with a rising human development index, especially in those under age 50 [3] . By 2035, the number of deaths from colon cancer and rectal cancer is projected to rise by 60.0% and 71.5%, respectively, due to population growth and aging [4] . Research deﬁnitively shows that early diagnosis and precise treatment of CRC signiﬁcantly improve patient survival rates [5, 6] . Recent advances in molecular biology have facilitated the delineation of critical genetic pathways that play a role in colorectal carcinogenesis [7, 8] . These pathways include the adenomatous polyposis coli (APC) pathway [9], the microsatellite instability (MSI) pathway [10], and the CpG island methylator phenotype (CIMP) pathway [11] . Understanding the intricate mechanisms of these pathways can provide valuable insights for developing targeted therapeutic strategies to combat colorectal cancer. In recent years, the rapid advancement of immune checkpoint inhibitor (ICI)-based immunotherapy has brought about a promising new era in anticancer treatment. ICIs enhance the antitumor immune response by disrupting the signaling of key immunosuppressive proteins like programmed cell death 1 (PD- 1), programmed cell death-1 ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) [12–14] . Some patients with melanoma, non-small-cell lung cancer (NSCLC), and other cancers show sustained responses [15–18] . Immunotherapy using ICI in CRC patients has shown promising safety andefﬁcacy outcomes. Approved immunotherapeutic agents for advanced CRC treatment include pembrolizumab

FAQs

What is the main goal of developing the FMRG_score system?

To use machine learning on TCGA and GEO data to evaluate modification patterns that affect clinical outcomes and immune characteristics in colorectal cancer, and to stratify patients reliably across immunotherapy cohorts.

How is CYP26A1 implicated in the colorectal cancer model?

CYP26A1 is upregulated in CRC tissues and is linked to increased proliferation, migration, and invasion, while contributing to an immunosuppressive tumor microenvironment.

What evidence supports the folate-based nine-gene risk model for CRC prognosis?

The study integrates bioinformatics with in vitro and in vivo experiments to connect folate metabolism–related features with patient prognosis, immune infiltration, checkpoint expression, therapy response, and drug sensitivity.

Sep 23, 2026

Uploaded by Stanley