Immunosuppressive tumor microenvironments (TMEs) create tremendous obstacles for an effective cancer therapy. Herein, we developed a melittin-RADA₃₂ hybrid peptide hydrogel loaded with doxorubicin (DOX) for a potent chemoimmunotherapy against melanoma through the active regulation of TMEs. The formed melittin-RADA₃₂-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.

中文翻译：

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注射肽水凝胶的肿瘤消融和治疗性免疫诱导

免疫抑制性肿瘤微环境（TME）为有效的癌症治疗创造了巨大的障碍。在这里，我们开发了一种载有阿霉素（DOX）的蜂毒素-RADA ₃₂杂合肽水凝胶，用于通过TME的主动调节来针对黑素瘤进行有效的化学免疫疗法。形成的蜂毒蛋白-RADA ₃₂ -DOX（MRD）水凝胶具有交织的纳米纤维结构，在体外和体内均表现出优异的生物相容性，受控的药物释放特性，并增强了对黑色素瘤细胞的杀伤作用。由于负载了蜂毒素和DOX，单剂量注射MRD水凝胶将原发性黑素瘤肿瘤的生长抑制了95％以上，并伴随着活化的自然杀伤细胞在肿瘤中的募集。此外，MRD水凝胶可以激活引流淋巴结的树突状细胞，特别是耗尽M2类肿瘤相关巨噬细胞（TAM），并产生活性的细胞毒性T细胞，进一步防御细胞抵抗剩余的肿瘤，从而提供针对皮下和转移性的有效抗癌功效体内肿瘤。多剂量MRD水凝胶注射可消灭50％的原发肿瘤，并在根除原始肿瘤后对肿瘤再发提供强大的免疫记忆作用。由于具有执行受控药物释放，调节先天免疫细胞，耗尽M2样TAM，直接抗癌和免疫刺激能力以及重塑免疫抑制TME的能力，MRD水凝胶可作为抗癌应用的强大工具。