Exploring bone-tumor interactions through 3D in vitro models: Implications for primary and metastatic cancers

Bone tissue serves as a perfect hosting site where metastatic cancer cells of the most prevalent cancer types, such as prostate and breast cancers, as well as the native bone sarcomas, can further proliferate, advancing the disease stage with the consequential decline of the patient's prognosis. Understanding how the bone niche interacts with tumor cells and the mechanisms leading to drug resistance is a crucial step for enabling the identification of effective cancer therapies. Nevertheless, bone tumor research and the development of new effective anticancer drugs have been hampered for a long time due to the limitations of preclinical models. Traditional 2D cultures and animal models have failed to accurately replicate the human bone cancer microenvironment, driving researchers to develop 3D in vitro bone models using tissue-engineered bone constructs and advanced technologies like microfluidics and additive manufacturing. While a complete reproduction of the bone tumor microenvironment (TME), including all relevant cell types, stromal elements, and biophysical cues, remains elusive, targeted inclusion of key components has advanced the physiological relevance of these models. The following review evaluates the biomimetic approaches that have been used to recapitulate the bone TME through 3D in vitro models, with particular attention to recent studies aimed at more accurately mimicking the complexity of bone TME, highlighting future directions and the advancements required to overcome present limitations.