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Immunoadjuvants, as an indispensable component of tumor vaccines, can observably enhance the magnitude, breadth, and durability of antitumor immunity. However, current immunoadjuvants suffer from different issues such as weak immunogenicity, inadequate cellular internalization, poor circulation time, and mono-functional bioactivity. Methods: Herein, we construct Fe 3+ -Shikonin metal-phenolic networks (FeShik) nanomedicines as immunogenic cell death (ICD) stimulants and multifunctional immunoadjuvants for tumor vaccination. The multifunctionality of FeShik nanomedicines is investigated by loading ovalbumin (OVA) as the model antigen to construct OVA@FeShik nanovaccines or 4T1 tumor cell fragment (TF) as homologous antigen to construct TF@FeShik nanovaccines. In vitro examinations including GSH responsive, •OH generation, colloid stability, cellular uptake, cytotoxicity mechanism of ferroptosis and necroptosis, ICD effect, the promotion of DC maturation and antigen cross-presentation were studied. In vivo observations including pharmacokinetics and biodistribution, antitumor effect, abscopal effect, immune memory effect, and biosafety were performed. Results: The presence of FeShik nanomedicines can significantly prolong the blood circulation time of antigens, increasing the bioavailability of antigens. Upon phagocytosis by tumor cells, FeShik nanomedicines can disassemble into Fe 2+ and Shikonin in response to tumor microenvironments, leading to ICD of tumor cells via ferroptosis and necroptosis. Consequently, ICD-released autologous tumor cell lysates and pro-inflammatory cytokines not only stimulate DC maturation and antigen cross-presentation, but also promote macrophage repolarization and cytotoxic T lymphocyte infiltration, resulting in the activation of adaptive immune responses toward solid tumors. Conclusion: In a word, our FeShik supramolecular nanomedicines integrate bioactivities of ICD stimulants and immunoadjuvants, such as eradicating tumor cells, activating antitumor immune responses, modulating immunosuppressive tumor microenvironments, and biodegradation after immunotherapy. Encouraged by the diversity of polyphenols and metal ions, our research may provide a valuable paradigm to establish a large library for tumor vaccination., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Nanovaccine-based immunotherapy has been considered as a major pillar to stimulate the host immune system to recognize and eradicate tumor cells as well as establish a long-term immune memory to prevent tumor relapse and metastasis. However, the weak specificity and low cross-presentation of antigens, as well as the immunosuppressive microenvironments of tumor tissues, are still the major obstacles on exerting the therapeutic performance of tumor nanovaccines sufficiently. Herein, we design and construct cytosine guanine dinucleotide (CpG) oligodeoxynucleotide (ODN)-loaded aluminum hydroxyphosphate nanoparticles covered by Fe-Shikonin metal-phenolic networks (MPNs) (Alum-CpG@Fe-Shikonin NPs) as personalized in situ nanovaccines for antitumor immunity. Upon internalization by tumor cells, the shell of Fe-Shikonin MPNs will disassemble into Fe 2+ and Shikonin to elicit the immunogenic cell death of tumor cells through ferroptosis and necroptosis. Then, dying tumor cell-released autologous tumor cell lysates will be absorbed by Alum NPs and codelivered with CpG ODN to professional antigen-presenting cells temporally and spatially to activate multistep cascade antitumor immune responses, including dendritic cell maturation, antigen cross-presentation, natural killer cell and cytotoxic T lymphocyte infiltrations, and tumor-associated macrophage repolarization. Benefiting from the synergistic effects of Alum NPs, CpG ODN, and Fe-Shikonin MPNs, our Alum-CpG@Fe-Shikonin NPs exhibit drastic cytotoxicity and accurate selectivity on eradicating primary tumor, strong abscopal effect on inhibiting distant tumor, and a long-term immune memory effect on preventing tumor metastasis and recurrence. Because our report provides a feasible strategy to in situ make full use of autologous tumor cell lysates, which present an entire spectrum of the patient's personal epitopes without complicated ex vivo processes, such as extraction, purification, and sequencing, it may promote the development of personalized nanovaccines for antitumor immunity.