Li Jie, Tan Chenfeng, Yang Jin, Xiang Zhongzheng, Wang Yan, Shen Meiling, Zhu Shunyao, He Tao, Liang Xiuqi, Shao Bianfei, Li Haijun, Li Zhike, Liu Lei, Gong Changyang
Department of Head and Neck Oncology, Cancer Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, China.
Department of Head and Neck Oncology, Cancer Center, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Biomaterials. 2025 May;316:123005. doi: 10.1016/j.biomaterials.2024.123005. Epub 2024 Dec 10.
Radiotherapy (RT) induced abscopal effect has garnered substantial attention, nevertheless, it is rarely observed in clinics, due to the tumor hypoxia-related radioresistance, inadequate immune stimulation, and immunosuppressive tumor microenvironment. Herein, we construct a radiotherapy-immunomodulated nanoplatform (THUNDER), which synergizes with RT and greatly triggers the generation of both hypoxic and normoxic tumor cells-derived tumor-associated antigens (TAAs), resulting in robust abscopal effect and sustained immune memory. THUNDER exhibits prolonged blood circulation and high tumor retention capacity. When combined with RT, THUNDER effectively destructs both hypoxic and normoxic tumor cells, facilitating the substantial release of TAAs from both cell types, which further promotes the maturation of dendritic cells (DCs), thus forming powerful immune stimulation and initiating systemic anti-tumor immunity. In murine models, the combination of THUNDER and RT efficiently suppresses the growth of triple-negative breast cancer. In addition, the further combination with PD-L1 blockade yields noteworthy suppression of distant metastasis and tumor recurrence, resulting in a 5.2-fold augmentation in CD8 T lymphocytes within distant tumors and a 2.8-fold increase in effector memory T cells in the spleen. In conclusion, the radiotherapy-immunomodulated nanoplatform presents an effective strategy for combating tumor metastases and recurrence by eliciting both hypoxic and normoxic TAAs, offering a significant avenue for radioimmunotherapy.
放射治疗（RT）诱导的远隔效应已引起广泛关注，然而，由于肿瘤缺氧相关的放射抗性、免疫刺激不足和免疫抑制性肿瘤微环境，该效应在临床上很少被观察到。在此，我们构建了一种放射治疗免疫调节纳米平台（THUNDER），它与放射治疗协同作用，极大地触发了缺氧和常氧肿瘤细胞衍生的肿瘤相关抗原（TAAs）的产生，从而产生强大的远隔效应和持续的免疫记忆。THUNDER具有延长的血液循环时间和高肿瘤滞留能力。与放射治疗联合使用时，THUNDER能有效破坏缺氧和常氧肿瘤细胞，促进两种细胞类型的TAAs大量释放，这进一步促进树突状细胞（DCs）的成熟，从而形成强大的免疫刺激并启动全身抗肿瘤免疫。在小鼠模型中，THUNDER与放射治疗的联合有效抑制了三阴性乳腺癌的生长。此外，与PD-L1阻断剂的进一步联合显著抑制了远处转移和肿瘤复发，导致远处肿瘤内的CD8 T淋巴细胞增加5.2倍，脾脏中的效应记忆T细胞增加2.8倍。总之，放射治疗免疫调节纳米平台通过引发缺氧和常氧TAAs，为对抗肿瘤转移和复发提供了一种有效的策略，为放射免疫治疗提供了一条重要途径。
