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

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. 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. 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).

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.