What does this research mean for the field?

A novel 9-gene lactylation-related risk signature effectively stratifies colorectal cancer patients by overall survival, tumor microenvironment immunosuppression, and sensitivity to specific chemotherapeutic and targeted agents. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to understand the role of a lactylation-related gene signature in the prognosis and treatment of colorectal cancer.

June 27, 2026Open Access

A novel lactylation-related gene signature deciphers the immunosuppressive microenvironment and stratifies precision therapy in colorectal cancer

Key Points

This research aims to understand the role of a lactylation-related gene signature in the prognosis and treatment of colorectal cancer.
Analyzed transcriptome data from TCGA and GEO cohorts and performed scRNA-seq analysis.
Constructed a lactylation-related gene risk signature using univariate Cox regression and LASSO analysis.
Evaluated the association between the risk signature and patient prognosis, immune infiltration, and treatment response.
A 9-gene prognostic signature was identified, with high-risk patients showing significantly worse overall survival.
High-risk tumors exhibited an immunosuppressive microenvironment with increased regulatory T cells and PIK3CA mutations.
Low-risk patients displayed high sensitivity to standard chemotherapeutics while high-risk patients had vulnerabilities to novel targeted agents.

Abstract

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality, largely due to the heterogeneity of the tumor microenvironment (TME) and the limited efficacy of immunotherapy in microsatellite stable (MSS) tumors. Histone lactylation, a post-translational modification derived from the Warburg effect, serves as a critical bridge linking metabolic reprogramming to gene regulation and immune evasion; however, its specific prognostic value and clinical implications in CRC remain to be fully elucidated. METHODS: In this study, we systematically analyzed transcriptome profiling data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts, supplemented by single-cell RNA sequencing (scRNA-seq) analysis and Human Protein Atlas (HPA) protein-level validation. By integrating univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox regression, we constructed a novel lactylation-related gene (LRG) risk signature. We extensively evaluated the association between this risk signature and patient prognosis, immune infiltration patterns, somatic mutations, and therapeutic sensitivity. RESULTS: A robust 9-gene prognostic signature (DHRS7, SPR, MBD2, RBM17, CSRP2, S100A4, TMSB4X, TKT, COPS4) was identified and corroborated at the protein level. Patients with high risk scores exhibited significantly worse overall survival (OS) across the training and two independent validation cohorts. Immunogenomic and scRNA-seq analyses revealed that high-risk tumors were characterized by an immunosuppressive and stromal-dense microenvironment-with stromal cells exhibiting the highest lactylation risk scores-enriched with regulatory T cells (Tregs), and frequently harbored PIK3CA mutations. Differential expression analysis indicated that this immune exclusion is structurally maintained by enriched extracellular matrix (ECM) organization and TGF-β signaling. Conversely, low-risk tumors displayed an inflamed phenotype with active antitumor immunity. Pharmacogenomic prediction identified distinct therapeutic stratifications: low-risk patients exhibited significant sensitivity to standard chemotherapeutics (fluorouracil, oxaliplatin) and EGFR/HER2 inhibitors (e.g., lapatinib, erlotinib). In contrast, high-risk patients showed specific vulnerabilities to novel targeted agents, including PI3K pathway inhibitors (TG-100-115, XL765), microenvironment-modulating agents (sildenafil, GANT-61), and epigenetic inhibitors (UNC0638). CONCLUSION: We established a novel lactylation-related risk signature that effectively stratifies CRC patients by prognosis and TME characteristics. By elucidating the crosstalk between metabolic dysregulation, stromal barriers, and immune exclusion, this study provides potential biomarkers and stratified therapeutic strategies-ranging from standard chemotherapy to targeted metabolic and stromal interventions-to optimize precision medicine for CRC patients.

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