Abstract

Although pancreatic ductal adenocarcinoma (PDAC) is generally considered an immunologically “cold” tumor, approximately 20% of cases can be classified as immune-hot. However, this immune-enriched (IE) phenotype does not confer a significant survival advantage, highlighting the need to investigate its underlying mechanisms and identify effective therapies. By integrating in vitro drug screening and in silico sensitivity prediction, we identified the HDAC inhibitor vorinostat (SAHA) as a potent sensitizer to chemoimmunotherapy specifically in the IE-PDAC. This effect was validated using T cell-organoid co-cultures and patient-derived xenografts with humanized immune systems. Mechanistically, abundant cytokines (TNF-α, FGF) in the IE tumor microenvironment promote FASN and PARP9 expression. This leads to free fatty acid accumulation and enhanced oxidative phosphorylation, supporting tumor cell survival. SAHA disrupts this “metabolic trap” by concurrently suppressing FASN and PARP9. Single-cell RNA sequencing revealed that the Gemcitabine-SAHA combination remodels the tumor microenvironment by enhancing CD8 + T cell function and depleting cancer-associated fibroblasts. Clinically, we defined a CD8 high /FASN high /PARP9 high signature that identifies an IE patient subgroup with poor survival, representing those most likely to benefit from the “Gemcitabine-Nivolumab-SAHA” triple-combination therapy.