zDHHC-mediated palmitoylation modification patterns and tumor immune microenvironment infiltration characterization in pancreatic cancer.

BACKGROUND

Protein palmitoylation, catalyzed by the zDHHC family of palmitoyltransferases, has emerged as a critical post-translational modification implicated in tumor progression. However, the comprehensive role of zDHHCs-mediated palmitoylation in molecular subtyping, prognosis, and immune microenvironment modulation in pancreatic cancer (PC) remains unclear.

METHODS

We systematically integrated multi-cohort transcriptome, single-cell RNA-seq, and somatic mutation data for PC. Bioinformatic analyses included molecular subtyping based on zDHHCs expression, differential gene expression, functional enrichment, CIBERSORTx-based immune infiltration analysis, single-cell trajectory inference, cell-cell communication networks, and construction/validation of a palmitoylation-related gene signature (PRGS) prognostic model.

RESULTS

Two robust molecular subtypes based on zDHHCs expression were identified, displaying significant differences in patient prognosis and immune infiltration. High zDHHCs activity was associated with immunosuppressive features, including decreased CD8+ T cell infiltration and enrichment of macrophages/eosinophils. Single-cell analyses revealed dynamic upregulation of zDHHCs genes during epithelial differentiation, especially in metastatic lesions, with trajectory and enrichment analyses implicating palmitoylation in proliferation, cell cycle, and chromatin remodeling. Cell-cell communication networks uncovered zDHHCs-dependent remodeling of SPP1-CD44 and MHC-II pathways, linked to immune suppression. A 7-gene PRGS (DCBLD2, CXCL5, ASPH, LAMC2, KRT6A, TOP2A, NPNT) prognostic model demonstrated robust predictive accuracy across independent cohorts, correlating with tumor mutation burden, TP53/KRAS mutation frequency, and activation of proteasome, pyrimidine metabolism, and immune evasion pathways.

CONCLUSIONS

zDHHCs-mediated palmitoylation and its regulatory gene network critically shape pancreatic cancer heterogeneity, immune microenvironment, and prognosis. The PRGS model provides a novel molecular tool for patient stratification and may inform the development of precision therapies targeting palmitoylation-driven pathways in PC.