Cancer-Associated Fibroblast-Centric Risk Model Predicts Immunotherapy Resistance in Pancreatic Cancer and Reveals PLOD2 as a Key Stromal Therapeutic Target.

BACKGROUND

Pancreatic neoplasms, particularly pancreatic adenocarcinoma (PAAD), are aggressive malignancies marked by extensive infiltration of cancer-associated fibroblasts (CAFs) and a highly complex tumor immune microenvironment. These pathological features are strongly associated with poor patient survival. However, the precise mechanisms underlying the role of CAFs in PAAD have not been determined.

METHODS

To systematically analyze the functions of CAFs in PAAD and their associations patient outcomes, an integrative approach combining multi-omics data with experimental validation was used.

RESULTS

Integrated weighted gene co-expression network and protein-protein interaction network analyses revealed CAF-related genes with functional significance. Experimental verification was performed to examine the influence of candidate CAF-related genes identified using multi-database analyses on tumor cell behavior. COL28A1, TGFB2, TGFBI, PLOD2, and COL22A1 were core genes closely associated with CAFs. Patients in the high-risk group demonstrated a higher immune escape ability and lower predictive response rate to immunotherapy than those in the low-risk group. Several potential targeted therapeutic compounds were identified, including dihydrorotenone and sorafenib. Single-cell RNA sequencing and expression analyses confirmed elevated expression of TGFBI and PLOD2 in CAFs. Functional experiments demonstrated that PLOD2 promotes tumor progression by regulating extracellular matrix remodeling.

CONCLUSIONS

This study provides insights into the molecular mechanisms underlying PAAD and establishes a theoretical foundation for the development of CAF-targeting therapeutic strategies.