Follistatin drives AR-independent prostate cancer through BMP signaling inactivation and microenvironmental remodeling

Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in advanced prostate cancer. Here we identify follistatin (FST), TGFβ superfamily antagonist, as a key driver of AR-independence and treatment resistance. During anti-AR therapy, cancer cells progressively lose the positive feedback loop between AR and BMP signaling, leading to FST upregulation that further suppresses this circuit. FST antagonizes BMP11-dependent AR maintenance and upregulates the lineage plasticity regulator SOX9, conferring resistance to enzalutamide while promoting stem-like properties and metastatic capabilities. FST also remodels the tumor microenvironment by driving osteoclastogenesis and compromising T cell effector function. Clinically, FST inversely correlates with PSA levels and associates with poor outcomes in enzalutamide-treated patients. We developed FST-Trap, which effectively neutralizes FST, resensitizes resistant tumors to AR-targeted therapy, and enhances immunotherapy efficacy. This establishes FST as both a biomarker and therapeutic target for AR-independent prostate cancer.