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We identify angiogenin (ANG) as a negative prognostic yet positive predictive biomarker for ALK5 inhibition combined with chemotherapy. In the randomized phase II H9H-MC-JBAJ trial, high baseline ANG predicted poor survival with gemcitabine alone but significant benefit from galunisertib addition. Mechanistic studies revealed that tumor-derived ANG binds epidermal growth factor receptor (EGFR) on tumor-associated macrophages (TAMs), activating RhoA-dependent cytoskeletal remodeling and autocrine ALK5\/TGF\u03b2 signaling. This drives M2-like polarization and Smad2-mediated transcription of tumor necrosis factor-\u03b1 (Tnf-\u03b1), which activates Nf-\u03baB in neighboring tumor cells, conferring chemoresistance. ALK5 inhibition suppressed TAM-derived Tnf-\u03b1, reduced M2 polarization, prevented Nf-\u03baB activation, and restored chemosensitivity in ANG-high models. Clinically, elevated ANG correlated with systemic TNF-\u03b1, and galunisertib reduced TNF-\u03b1 exclusively in ANG-high patients, with reductions associated with markedly improved survival. These findings define an ANG\u2013EGFR\u2013TGF\u03b2\u2013TNF-\u03b1 axis in TAMs as a stromal driver of PDAC chemoresistance, and provide a mechanistic rationale for the development of combination strategies targeting ALK5 signaling in ANG-high PDAC patients.<\/jats:p>","DOI":"10.1038\/s41388-026-03774-0","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T01:14:50Z","timestamp":1776129290000},"page":"1901-1913","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["EGFR ligand Angiogenin predicts response to ALK5 inhibition in pancreatic cancer via a TNF-\u03b1 paracrine axis in tumor-associated macrophages"],"prefix":"10.1038","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5544-7286","authenticated-orcid":false,"given":"Silvia","family":"Pietrobono","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2606-2977","authenticated-orcid":false,"given":"Veronica","family":"De Vita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Mangiameli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4107-6680","authenticated-orcid":false,"given":"Antonino","family":"Aparo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora San","family":"Lorenzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3634-6527","authenticated-orcid":false,"given":"Alice","family":"Bonato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Bertolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enza","family":"Scarlato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Casalino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Quinzii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Zecchetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Melisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"3774_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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The other authors have declared that no conflict of interest exists.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}