Hijacking the bone niche: mechanistic insights into bone metastasis in breast cancer

Abstract

Breast cancer is one of the most common malignant tumors worldwide, with metastasis being the leading cause of mortality among patients. Bone is the most frequent site of metastasis in breast cancer, accounting for approximately 70% of metastatic cases. Before bone metastasis, primary breast cancer cells secrete circulating factors (e.g., exosomal RNAs, metabolites, and cytokines) to precondition the bone microenvironment and establish a supportive pre-metastatic niche (PMN). After dissemination, tumor cells further hijack the bone niche by releasing receptor activator of nuclear factor-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and transforming growth factor-β (TGF-β), thereby disrupting bone homeostasis through osteoclast activation and osteoblast dysregulation. Bone matrix degradation subsequently releases latent growth factors that in turn fuel tumor cell proliferation, thereby establishing a self-reinforcing vicious cycle. Meanwhile, breast cancer cells actively induce local immunosuppression and promote angiogenesis, remodeling a pro-tumor bone niche conducive to metastatic outgrowth. This review highlights the immunosuppressive roles of immune cells and key molecular mediators in the vicious cycle, systematically analyzes intercellular crosstalk within both the bone PMN and the hijacked niche, and summarizes emerging therapeutic strategies (including novel targeted inhibitors, immune-based combinations, epigenetic modulation, and nanomedicines) beyond conventional treatments. These insights provide a theoretical framework and identify promising therapeutic targets for future treatment strategies against breast cancer bone metastasis.