Immunosuppressive tumor microenvironments (TMEs) create tremendous obstacles for an effective cancer therapy. Herein, we developed a melittin-RADA hybrid peptide hydrogel loaded with doxorubicin (DOX) for a potent chemoimmunotherapy against melanoma through the active regulation of TMEs. The formed melittin-RADA-DOX (MRD) hydrogel has an interweaving nanofiber structure and exhibits excellent biocompatibility, controlled drug release properties both in vitro and in vivo, and an enhanced killing effect to melanoma cells. A single-dose injection of MRD hydrogel retarded the growth of primary melanoma tumors by more than 95% due to loaded melittin and DOX, with concomitant recruitment of activated natural killer cells in the tumors. Furthermore, MRD hydrogel can activate dendritic cells of draining lymph nodes, specifically deplete M2-like tumor-associated macrophages (TAMs), and produce active, cytotoxic T cells to further defend the cells against remaining tumors, providing potent anticancer efficacy against subcutaneous and metastatic tumors in vivo. Multidose injection of MRD hydrogel eliminated 50% of the primary tumors and provided a strong immunological memory effect against tumor rechallenge after eradication of the initial tumors. Owing to its abilities to perform controlled drug release, regulate innate immune cells, deplete M2-like TAMs, direct anticancer and immune-stimulating capabilities, and reshape immunosuppressive TMEs, MRD hydrogel may serve as a powerful tool for anticancer applications.

Radiotherapy (RT) is routinely used in cancer treatment, but expansion of its clinical indications remains challenging. The mechanism underlying the radiation-induced bystander effect (RIBE) is not understood and not therapeutically exploited. We suggest that the RIBE is predominantly mediated by irradiated tumor cell–released microparticles (RT-MPs), which induce broad antitumor effects and cause immunogenic death mainly through ferroptosis. Using a mouse model of malignant pleural effusion (MPE), we demonstrated that RT-MPs polarized microenvironmental M2 tumor-associated macrophages (M2-TAMs) to M1-TAMs and modulated antitumor interactions between TAMs and tumor cells. Following internalization of RT-MPs, TAMs displayed increased programmed cell death ligand 1 (PD-L1) expression, enhancing follow-up combined anti–PD-1 therapy that confers an ablative effect against MPE and cisplatin-resistant MPE mouse models. Immunological memory effects were induced.

Aims To explore the involvement of NOD‐like receptor protein 3 (NLRP3) inflammasome and M1 macrophage in root resorption (RR). Methods A rat RR model was established by excessive orthodontic force. After different force‐loading time, the expression levels of NLRP3, caspase‐1, and interleukin‐1β (IL‐1β) and distribution of M1 macrophages were analysed by immunohistochemistry and immunofluorescence staining in vivo. Then, the mechanism of NLRP3 activation was further verified by macrophage and human periodontal ligament cell (hPDLC) co‐culture system in vitro. The production levels of NLRP3, caspase‐1, pro‐caspase‐1, and IL‐1β in M1 macrophages in the co‐culture system were detected by Western blot, and the polarization of CD68+IL‐1β+ M1 macrophages was detected by immunofluorescence staining. Results In the rat RR model, NLRP3, caspase‐1, IL‐1β, and M1 macrophages were expressed in periodontal ligament, mainly concentrated around RR areas. Force‐pre‐treated hPDLCs promoted M1 macrophage polarization and the production of NLRP3, caspase‐1, and IL‐1β in M1 macrophages in co‐culture system. When MCC950, an inhibitor of NLRP3 inflammasome, was added, NLRP3 activation and M1 macrophage polarization were inhibited. Conclusions In periodontal tissues, hPDLCs stimulated by force promoted M1 macrophage polarization and increased IL‐1β production by activating NLRP3 inflammasome in M1 macrophages, thus initiating the occurrence of RR.