EGFR ligand Angiogenin predicts response to ALK5 inhibition in pancreatic cancer via a TNF-α paracrine axis in tumor-associated macrophages

Abstract Transforming growth factor-β (TGFβ) receptor ALK5 inhibition has shown promise in pancreatic ductal adenocarcinoma (PDAC), but predictive biomarkers remain undefined. 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/TGFβ signaling. This drives M2-like polarization and Smad2-mediated transcription of tumor necrosis factor-α (Tnf-α), which activates Nf-κB in neighboring tumor cells, conferring chemoresistance. ALK5 inhibition suppressed TAM-derived Tnf-α, reduced M2 polarization, prevented Nf-κB activation, and restored chemosensitivity in ANG-high models. Clinically, elevated ANG correlated with systemic TNF-α, and galunisertib reduced TNF-α exclusively in ANG-high patients, with reductions associated with markedly improved survival. These findings define an ANG–EGFR–TGFβ–TNF-α 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.