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Here, we stratified PDA tumors by mRNA translation rates, a frequently dysregulated step in gene expression, using translatome profiling of 27 patient\u2010derived xenografts (PDXs). Unsupervised analysis revealed a distinct tumor subset with low global protein synthesis but sustained translation of Integrated Stress Response (ISR) mRNAs, including ATF4. These ISR\u2010activated cancer cells exhibited broad chemoresistance and apoptosis resistance, yet were auxotrophic for serine due to loss of PHGDH and CBS expression, impairing serine and cysteine biosynthesis. This vulnerability correlated with improved overall survival in patients with low expression of both enzymes. Notably, cancer\u2010associated fibroblasts (CAFs) reprogrammed by ISR\u2010activated cells, shifting from myCAF to iCAF phenotype with reduced collagen synthesis and glycine\u2010to\u2010serine conversion, produced serine and sustained tumor growth in amino acid\u2010depleted environments. Our findings demonstrate the power of translatome profiling to reveal stable, drug\u2010resistant PDA cell states and identify a targetable CAF\u2010tumor metabolic symbiosis, opening new avenues for therapeutic intervention in this highly lethal malignancy.<\/jats:p>","DOI":"10.1002\/advs.202515740","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T06:45:47Z","timestamp":1771397147000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine\u2010dependent Tumor Subset Under Metabolic Relationships With CAFs."],"prefix":"10.1002","volume":"13","author":[{"given":"Sauyeun","family":"Shin","sequence":"first","affiliation":[{"name":"Cancer Research Center of Toulouse (CRCT) INSERM U1037 ERL5294 CNRS University of Toulouse  Toulouse France"},{"name":"Equipe Labellis\u00e9e Ligue Contre le 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