Biomimetic bone niche reconstructs proliferation-inhibited and therapy-resistant bone-metastatic prostate cancer

Prostate cancer bone metastases often harbor a rare subset of tumor cells with suppressed proliferation, contributing to therapy resistance and disease relapse. However, the lack of physiologically relevant in vitro models has hindered mechanistic and therapeutic advances. Here, we engineered a 3D bone-like microenvironment by integrating calcium phosphate scaffolds, decellularized extracellular matrix (dECM), mesenchymal stem cells (MSCs), and osteoblasts. This biomimetic niche induced a proliferation-inhibited state in prostate cancer cells, closely mirroring transcriptomic signatures identified from patient-derived single-cell RNA sequencing datasets. Tumor cells in this niche also displayed enzalutamide resistance, accompanied by metabolic reprogramming and activation of pro-survival signaling. This platform provides a clinically relevant tool for modeling bone metastatic prostate cancer and accelerating the development of therapies targeting resistant tumor states. • A novel 3D bioprinted biomimetic bone microenvironment (BME) was engineered, recapitulating the proliferation-inhibited tumor phenotype in clinical prostate cancer bone metastases. • This platform integrates a CPC scaffold mimicking trabecular bone and dECM hydrogel, showing robust biocompatibility and osteoinductive properties. • The biomimetic BME suppressed prostate cancer cell proliferation in vitro and in vivo, inducing G0/G1 arrest and reducing tumor growth. • Transcriptomic profiling of tumor cells in the BME revealed downregulated cell cycle/proliferative pathways and altered metabolism, matching patient scRNA-seq data from bone metastatic prostate cancer. • The 3D-printed BME model conferred enzalutamide resistance to prostate cancer cells, highlighting microenvironment-driven metabolic reprogramming and pro-survival pathways for therapeutic evasion.