Functional studies confirmed RARRES1 overexpression in gemcitabine-resistant cells, and pan-cancer analysis established RARRES1 as a new biomarker for poor prognosis across multiple cancer types.<h4>Conclusions</h4>Our work defines a chemotherapy-resistant and metastasis-enriched malignant epithelial subpopulation in PDAC that drives disease progression through an immune-cold niche. Here, RARRES1 is linked to cancer.