Our work defines a chemotherapy-resistant and metastasis-enriched malignant epithelial subpopulation in PDAC that drives disease progression through an immune-cold niche. We identify RARRES1 as a pivotal regulator of this process, contributing to both therapy resistance and immune exclusion, and propose it as a novel pan-cancer prognostic biomarker. These findings reveal a targetable cellular mechanism underlying poor treatment response in PDAC.