Pei Xu,Yuan Gu,Chenze Li,Jiahao Shen,Xiaju Cheng,Leshuai W. Zhang,Yangyun Wang,Yong Wang
Tumor in situ vaccination (ISV) strategies have emerged in clinical trials as promising approaches, involving the release of tumor antigens through local radiotherapy and intratumorally adjuvant injections. However, the current fabrication strategy for achieving a sustainable immune response to ISV remains a pressing challenge. In this study, we present an empowered sustainable ISV method for antitumor therapy using 177Lu-labeled manganese-doped mesoporous hydroxyapatite (177Lu/Mn-HAP) microspheres. The ISV enables the sustained utilization of tumor antigens, leading to the activation of dendritic cells and polarization of macrophages toward the M1 subtype. Consequently, it facilitates the generation of potent CD8+ T-cell responses, enhancing the antitumor effects of internal radiation in both primary and distant tumors. Importantly, this approach achieves complete remission in all tumor-bearing mice and stimulates immune memory to prevent tumor recurrence. Our study highlights a universal and safe ISV strategy capable of inducing potent tumor-specific and sustainable immune response.
Pei Pei,Yu Zhang,Yunchun Jiang,Wenhao Shen,Hua Chen,Sai Yang,Yanxiang Zhang,Xuan Yi,Kai Yang
Biomaterial-based pleiotropic immune activation may effectively improve the response rate of immunotherapy and enhance the therapeutic effect of the tumor. Bacteria as a natural carrier have demonstrated great advantages in tumor targeted delivery and immune activation of the body. Herein, we construct an inactivated bacteria vector with 125I/131I labeling (125I-VNP/131I-VNP), which could retain radioiodine at the tumor site for a long time and deliver it into tumor cells and a tumor-associated macrophage (TAM), thus achieving efficient internal radioisotope therapy (IRT) of the primary tumor with good biosafety. More importantly, 131I-VNP-mediated local IRT could further stimulate robust systemic antitumor immune responses via activation of the cGAS-STING pathway of innate immunity and promotion of the maturation of DC cells for T-cell-dominated adaptive immunity. After combination with systemic checkpoint blockade therapy (αPD-L1), 131I-VNP, which induces the up-regulation of PD-L1 expression in the distant tumor, could lead to the inhibition of in situ colon cancer and protection against tumor rechallenge. Our strategy pioneers the use of an inactivated bacteria vector as a bridge to cleverly connect radiotherapy and immunotherapy and provide an enlightening idea for radio-immunotherapy mediated by pleiotropic immune activation functions of bacterial vectors.
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