Metals are an emerging topic in cancer immunotherapy that have shown great potential in modulating cancer immunity cycle and promoting antitumor immunity by activating the intrinsic immunostimulatory mechanisms which have been identified in recent years. The main challenge of metal‐assisted immunotherapy lies in the fact that the free metals as ion forms are easily cleared during circulation, and even cause systemic metal toxicity due to the off‐target effects. With the rapid development of nanomedicine, metal‐based smart nanosystems (MSNs) with unique controllable structure become one of the most promising delivery carriers to solve the issue, owing to their various endogenous/external stimuli‐responsiveness to release free metal ions for metalloimmunotherapy. In this review, the state‐of‐the‐art research progress in metal‐related immunotherapy is comprehensively summarized. First, the mainstream mechanisms of MSNs‐assisted immunotherapy will be delineated. The immunological effects of certain metals and categorization of MSNs with different characters and compositions are then provided, followed by the representative exemplar applications of MSNs in cancer treatment, and synergistic combination immunotherapy. Finally, we conclude this review with a summary of the remaining challenges associated with MSNs and provide the authors' perspective on their further advances.

Sun D, et al. Korean J Radiol. 2020 Jul;21(7):859-868. https://doi.org/10.3348/kjr.2020.0293

Background: The prognosis for hepatocellular carcinoma (HCC) remains suboptimal, characterized by high recurrence and metastasis rates. Although metalloimmunotherapy has shown potential in combating tumor proliferation, recurrence and metastasis, current apoptosis-based metalloimmunotherapy fails to elicit sufficient immune response for HCC. Results: A smart responsive bimetallic nanovaccine was constructed to induce immunogenic cell death (ICD) through pyroptosis and enhance the efficacy of the cGAS-STING pathway. The nanovaccine was composed of manganese-doped mesoporous silica as a carrier, loaded with sorafenib (SOR) and modified with MIL-100 (Fe), where Fe³⁺, SOR, and Mn²⁺ were synchronized and released into the tumor with the help of the tumor microenvironment (TME). Afterward, Fe³⁺ worked synergistically with SOR-induced immunogenic pyroptosis (via both the classical and nonclassical signaling pathways), causing the outflow of abundant immunogenic factors, which contributes to dendritic cell (DC) maturation, and the exposure of double-stranded DNA (dsDNA). Subsequently, the exposed dsDNA and Mn²⁺ jointly activated the cGAS-STING pathway and induced the release of type I interferons, which further led to DC maturation. Moreover, Mn²⁺-related T1 magnetic resonance imaging (MRI) was used to visually evaluate the smart response functionality of the nanovaccine. Conclusion: The utilization of metallic nanovaccines to induce pyroptosis-mediated immune activation provides a promising paradigm for HCC treatment.