AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high incidence rates of metastasis and cachexia. High circulating activin A, a homodimer of inhibin βA subunits that are encoded by INHBA gene, predicts poor survival among PDAC patients. However, it still raises the question of whether activin A suppression renders favorable PDAC outcomes. Here, the authors demonstrate that activin A is abundantly detected in tumor and stromal cells on PDAC tissue microarray and mouse PDAC sections. In orthotopic male mice, activin A suppression, which is acquired by tumor‐targeted Inhba siRNA using cholesterol‐modified polymeric nanoparticles, retards tumor growth/metastasis and cachexia and improves survival when compared to scramble siRNA‐treated group. Histologically, activin A suppression coincides with decreased expression of proliferation marker Ki67 but increased accumulation of α‐SMAhighfibroblasts and cytotoxic T cells in the tumors. In vitro data demonstrate that activin A promotes KPC cell proliferation and induces the downregulation of α‐SMA and upregulation of IL‐6 in pancreatic stellate cells (PSC) in the SMAD3‐dependent mechanism. Moreover, conditioned media from activin A‐stimulated PSC promoted KPC cell growth. Collectively, our data provide a mechanistic basis for tumor‐promoting roles of activin A and support therapeutic potentials of tumor activin A suppression for PDAC.