Carnitine palmitoyltransferase 2 as a novel prognostic biomarker and immunoregulator in colorectal cancer

Abstract

Background: Metabolic interventions are critical for enhancing immunotherapy efficacy, but reliable metabolic targets remain absent for colorectal cancer (CRC). This study aims to investigate the interplay between metabolic and immunological factors in CRC, identify metabolic immunoregulatory molecules, and propose targets for prognostic and therapeutic applications.

Methods: Immune infiltration and metabolic pathways in CRC were analyzed using CIBERSORT and gene set variation analyses. Cox regression identified survival-related metabolic genes, forming a metabolic-related gene prognostic index (MRGPI), which was validated through survival analysis, timeROC, GSEA, CIBERSORT, and TIDE. Hub genes in the MRGPI were assessed using enrichment and co-expression network analyses. The expression of carnitine palmitoyltransferase 2 (CPT2) was validated through multiplex immunofluorescence of tissue microarrays. While its role was examined by western blot, CCK-8 assay, flow cytometry, qRT-PCR, Elisa, chemotaxis assays, etc. RESULTS: Fatty acid oxidation (FAO) pathways were significantly altered in CRC and correlated with immune cell infiltration and patient survival. The MRGPI, constructed from five survival-related metabolic genes, demonstrated strong prognostic and immunotherapeutic predictive value. Moreover, CPT2, a key hub gene in the MRGPI, whose lower expression in plasma cells predicts unfavorable patients' survival and could be an independent prognostic indicator, while its knockout in tumor cells significantly increases the infiltrating levels of CD8⁺ T cells via promoting the release of CCL25.

Conclusion: The FAO-dominated MRGPI is a promising biomarker for predicting patient outcomes and immunotherapy response. CPT2 holds potential as a prognostic marker and therapeutic target for CRC metabolic immunotherapy.

Keywords: Carnitine palmitoyltransferase 2; Colorectal cancer; MRGPI.