Reprogramming the Immunosuppressive Osteosarcoma Microenvironment with Metal-Based Nanoplatforms: A 5-Year Systematic Review

Background/Objectives: Osteosarcoma (OS) is the most common primary malignant bone tumor and remains difficult to treat when recurrent or metastatic. Its immunologically “cold” tumor microenvironment (TME) limits the activity of conventional immunotherapies. Metal-containing nanosystems have therefore been investigated as platforms that combine targeted delivery with immune modulation. Because the available literature includes both vaccine-like systems and broader multifunctional nanotherapeutics, this systematic review evaluates metal-based immunomodulatory nanoplatforms and distinguishes mechanistic immune reprogramming evidence from therapeutic outcome evidence. Methods: PubMed/MEDLINE, Scopus, and Web of Science were searched for preclinical in vivo OS studies, published from 1 May 2021 through 30 April 2026. Thirteen studies met the eligibility criteria. Data were extracted on model characteristics, nanoparticle architecture, targeting and release mechanisms, therapeutic cargo, immune/TME endpoints, tumor outcomes, metastasis-related outcomes, and reported toxicity. Results: Zinc-containing zeolitic imidazole framework-8 (ZIF-8) platforms were used in six studies and manganese-containing platforms in five, with one platform incorporating both metals. Reported mechanisms included cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, immunogenic cell death, myeloid cell modulation, metabolic remodeling, and increased T-cell infiltration. All included studies reported primary tumor inhibition under their respective experimental conditions; two studies reported a distal tumor or metastasis-related endpoint. No overt systemic toxicity was reported under the short-term experimental conditions assessed, although safety evaluation was generally limited to measures such as body weight, blood tests, or organ histology. Conclusions: Metal-based immunomodulatory nanoplatforms are a promising preclinical strategy for remodeling the OS TME. However, substantial heterogeneity in models, interventions, comparators, immune assays, and toxicity assessment precludes claims of comparative material-specific efficacy or established systemic safety. More standardized orthotopic and metastatic models, durable immune-response assessment, and comprehensive pharmacokinetic and long-term biosafety studies are needed before clinical translation.