Phenylalanine Hydroxylase as a Prognostic Marker in Pancreatic Cancer: Insights into Tumor Metabolism and Immune Microenvironment.

INTRODUCTION

Tumor metabolism-related genes participate in tumor metabolic reprogramming and reshape the tumor microenvironment (TME), thereby influencing tumor progression and patient prognosis. However, studies investigating pancreatic cancer (PC) are limited. This study examines how aromatic amino acid metabolism and its key genes influence the TME and prognosis in PC.

METHOD: We performed an integrated multi-omics analysis of aromatic amino acid metabolism-related genes in various cancers. Patients in the PC cohort were classified into two subtypes with significant metabolic heterogeneity. Analysis of survival outcomes, metabolic pathway activity, tumor microenvironment characteristics, and drug sensitivity in patients with the two subtypes. Key driver genes in aromatic amino acid metabolism were identified and validated in a separate cohort of 150 resected PC patients using immunohistochemistry, with assessments of gene expression, immune cell infiltration, fibroblast markers, and immune checkpoint levels.

RESULTS

Genes related to aromatic amino acid metabolism show unique changes and prognostic significance in various s cancers. Lower metabolism of these amino acids is linked to better clinical outcomes. In an independent validation cohort, the expression of phenylalanine hydroxylase (PAH) is associated with overall survival (OS) (p<0.05) and disease-free survival (DFS) (p<0.05) in patients with PC. Both univariate analysis (HR 2.017; p = 0.001) and multivariate analysis (HR 1.653; p = 0.028) corroborate its role as an independent prognostic factor. PAH expression correlated positively with CD8+ TILs (p=0.002) and negatively with FAP (p<0.05) in CAFs.

DISCUSSIONS: This study identifies PAH as a critical suppressor of pancreatic cancer progression, potentially by remodeling the tumor immune microenvironment through the enhancement of CD8+ T-cell infiltration and the suppression of FAP+ cancer-associated fibroblasts. Although these findings highlight the prognostic and therapeutic potential of PAH, further mechanistic studies and preclinical validation are necessary to translate these insights into clinical applications.

CONCLUSION

This study is the first to reveal PAH as a metabolic immunomodulator and an independent prognostic factor in postoperative PC patients. PAH may affect prostate cancer outcomes by altering the tumor microenvironment.