Hypofractionated radiotherapy (HRT) is a promising approach for tumor treatment, owing to its straightforward elimination of tumor cells and stimulation of immunogenic cell death. However, clinical application of HRT is hindered by the inherent radio-resistance and inadequate immune activation. Herein, an injectable hydrogel platform was reported, enabling a cascade amplification of radiosensitization and immune activation to potentiate HRT. The hydrogel with encapsulated TLR7/8 agonist R848 is in situ constructed in tumor via L-norvaline-based polymer (LNP, a gelator). During HRT, the released L-norvaline from LNP suppresses L-arginine consumption through arginase 1 (ARG1) pathway, sparing adequate L-arginine that was used for radiosensitizer nitric oxide (NO) production by inducible NO synthase (iNOS). Meanwhile, R848 repolarizes tumor-associated macrophages (TAMs) from M2 type with rich ARG1 to M1 type with rich iNOS, reinforcing NO production and disrupting M2-type TAMs-induced radio-resistance and immunosuppression. Therefore, the hydrogel demonstrates a cascade regulation of radio-sensitization and immune activation, achieving powerful inhibition of tumor growth and tumor metastasis. This hydrogel provides a novel approach to potentiate HRT, holding great promise in clinical application.

中文翻译：

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用于癌症放射治疗的水凝胶放射增敏和免疫激活级联放大


大分割放射治疗（HRT）是一种有前途的肿瘤治疗方法，因为它可以直接消除肿瘤细胞并刺激免疫原性细胞死亡。然而，HRT 固有的放射抗性和免疫激活不足阻碍了其临床应用。本文报道了一种可注射水凝胶平台，能够级联放大放射增敏和免疫激活，从而增强 HRT。封装有 TLR7/8 激动剂 R848 的水凝胶是通过基于 L-正缬氨酸的聚合物（LNP，一种胶凝剂）在肿瘤中原位构建的。在 HRT 期间，LNP 释放的 L-正缬氨酸通过精氨酸酶 1 (ARG1) 途径抑制 L-精氨酸消耗，从而保留足够的 L-精氨酸，用于通过诱导型 NO 合酶 (iNOS) 产生放射增敏剂一氧化氮 (NO)。同时，R848使肿瘤相关巨噬细胞（TAM）从富含ARG1的M2型重新极化为富含iNOS的M1型，增强NO产生并破坏M2型TAM诱导的放射抗性和免疫抑制。因此，水凝胶表现出放射增敏和免疫激活的级联调节，实现了对肿瘤生长和肿瘤转移的强大抑制。这种水凝胶提供了一种增强 HRT 的新方法，在临床应用中具有广阔的前景。