Immunotherapy and postoperative bone defect repair strategies based on osteosarcoma tumor microenvironment characteristics: balancing antitumor effects and promotion of bone regeneration

Abstract Advances in orthopedic biomaterials have significantly improved the bone regeneration domain; however, postoperative bone defect repair after bone tumor resection—particularly for osteosarcoma, a common primary malignant bone tumor in children and adolescents—remains a critical exception. Osteosarcoma’s aggressiveness, early metastatic propensity and immunosuppressive tumor microenvironment (OS-TME) limit conventional therapies, yielding poor prognosis in recurrence or metastasis cases. Although traditional tissue engineering promotes bone regeneration, it inadvertently sustains tumor growth, recurrence and metastasis via cytokines such as TGF-β1, VEGF and BMP-2. Mesenchymal stem cells and induced pluripotent stem cells worsen this by inducing M2 macrophage polarization, creating a tumor-supportive immune niche. Our prior research on biodegradable magnesium for bone repair showed Mg2+ enhances osteogenesis by activating PI3K/AKT via the TRPM7 channel; yet, TRPM7 as an oncogene links to tumor invasion and metastasis, posing risks for magnesium-based scaffolds in osteosarcoma defect repair. Thus, traditional tissue engineering’s three core elements (seed cells, scaffolds, cytokines) fail to meet dual needs of anti-tumor efficacy and bone regeneration in post-tumor defects. Recent tumor immunology breakthroughs have driven immuno-tissue engineering’s rise, offering new opportunities for osteosarcoma defect repair. Still, limited understanding of OS-TME mechanisms hinders clinical translation. This review delineates OS-TME’s immune landscape, covering immune cells (e.g. TAMs, Tregs, myeloid-derived suppressor cells), checkpoints (e.g. PD-1, CTLA-4, CD47) and immunotherapies and explores their tissue engineering integration through sequential release, spatiotemporal targeting, immune modulation and multimodal analyses (e.g. single-cell RNA sequencing, spatial transcriptomics) to optimize material design. We propose immune modulation as a novel ‘fourth element’ in tissue engineering, beyond the conventional seed cells, scaffolds and cytokines framework. This exposition lays a theoretical foundation for osteosarcoma immuno-tissue engineering repair and inspires innovative biomaterial solutions.