A ‘three-axis synergy’ immunotherapeutic strategy for malignant bone tumors based on natural bioactives and bioactive materials

This review presents an innovative "three-axis synergy" immunotherapeutic strategy for malignant bone tumors, combining natural bioactives with bioactive materials to overcome the challenges posed by the immunosuppressive microenvironment (IME) of tumors. Malignant bone tumors create an IME characterized by immune evasion, bone destruction, and physicochemical dysregulation, which limits the effectiveness of conventional therapies. Natural bioactives, known for their immunomodulatory effects, can potentially reprogram the IME, but their clinical application is hindered by low bioavailability and limited targeting efficiency. Bioactive materials, such as scaffolds and nanoparticles, can improve the delivery, retention, and targeted release of these bioactives, while also supporting bone regeneration. By combining natural bioactives with bioactive materials, this synergistic approach offers a dual-functional therapeutic platform that not only targets immune suppression but also promotes bone repair. This strategy addresses the key barriers of the IME, including immune imbalance, bone resorption, and physicochemical abnormalities. Although challenges remain in the clinical translation of these natural bioactives, their integration with bioactive materials provides a promising direction for improving treatment outcomes of malignant bone tumors. This approach offers new insights into the future of cancer immunotherapy and bone regeneration.