The bone cancer microenvironment is a complex and dynamic ecosystem involved in tumor initiation, progression, metastasis, and therapeutic resistance. This intricate milieu, comprising bone cells, immune cells, stromal components, the extracellular matrix, and soluble factors, orchestrates a unique interplay that can either suppress or promote malignancy. Aberrant signaling within the bone cancer microenvironment fuels the "vicious cycle" of bone destruction and tumor growth characteristic of primary and metastatic bone cancers. Understanding the multifaceted cellular and molecular interactions within this distinct niche is crucial for deciphering the mechanisms driving disease pathogenesis and identifying novel therapeutic targets.

The primary challenge in treating bone cancers lies in their intricate interactions with the surrounding microenvironment, which often fosters aggressive tumor behavior and limits the efficacy of conventional therapies. The complex interplay of cellular and acellular components within the bone cancer microenvironment contributes to drug resistance, immune evasion, and the debilitating bone destruction characteristic of these malignancies. Despite advances in surgery, chemotherapy, and radiation, patient outcomes, particularly for metastatic disease and relapsed cases, remain unsatisfactory. Recent progress in understanding the bone cancer microenvironment has revealed critical signaling pathways and cellular interactions that drive tumor progression. In particular, the dysregulation of osteoclast and osteoblast activity, the recruitment and polarization of tumor-associated macrophages, and the remodeling of the bone extracellular matrix by cancer-associated fibroblasts (CAFs) have emerged as key therapeutic targets. More recently, research has focused on investigating the role of nerve fibers in the bone tumor microenvironment and their influence on cancer progression and pain. Furthermore, the role of non-cellular components, including exosomes and the influence of the bone-specific mineralized matrix, is increasingly recognized. This Research Topic aims to consolidate cutting-edge research focused on dissecting the multifaceted complexity of the bone tumor microenvironment to widen the landscape of potential therapeutic targets and ultimately improve patient outcomes.

This Research Topic aims to gather original research articles, reviews, and short communications addressing one or more of the following topics:

• Tumor-stroma interaction in primary bone tumors and bone metastasis;

• Molecular signaling within the bone tumor microenvironment affecting cancer behavior and drug resistance;

• The significance of physical and chemical properties of bone tumor microenvironment, including interstitial fluid pressure, hypoxia, cancer-associated acidosis, in modulating cancer behavior and its relevance for therapeutic intervention;

• Role of the immune landscape in bone tumor progression and response to therapy;

• Advancements in targeting bone tumor microenvironment;

• Neural involvement in bone cancer progression and pain

• Preclinical models to investigate cellular and molecular interactions in the bone tumor microenvironment

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Unraveling the Complexity of Bone Cancer Microenvironment: Insights for Novel Therapeutic Avenues