PDF(Pubmed)
Abstract：
Rationale: Surgical resection is a primary treatment for solid tumors, but high rates of tumor recurrence and metastasis post-surgery present significant challenges. Manganese (Mn2+), known to enhance dendritic cell-mediated cancer immunotherapy by activating the cGAS-STING pathway, has potential in post-operative cancer management. However, achieving prolonged and localized delivery of Mn2+ to stimulate immune responses without systemic toxicity remains a challenge. Methods: We developed a post-operative microenvironment-responsive dendrobium polysaccharide hydrogel embedded with Mn2+-pectin microspheres (MnP@DOP-Gel). This hydrogel system releases Mn2+-pectin microspheres (MnP) in response to ROS, and MnP shows a dual effect in vitro: promoting immunogenic cell death and activating immune cells (dendritic cells and macrophages). The efficacy of MnP@DOP-Gel as a post-surgical treatment and its potential for immune activation were assessed in both subcutaneous and metastatic melanoma models in mice, exploring its synergistic effect with anti-PD1 antibody. Result: MnP@DOP-Gel exhibited ROS-responsive release of MnP, which could exert dual effects by inducing immunogenic cell death of tumor cells and activating dendritic cells and macrophages to initiate a cascade of anti-tumor immune responses. In vivo experiments showed that the implanted MnP@DOP-Gel significantly inhibited residual tumor growth and metastasis. Moreover, the combination of MnP@DOP-Gel and anti-PD1 antibody displayed superior therapeutic potency in preventing either metastasis or abscopal brain tumor growth. Conclusions: MnP@DOP-Gel represents a promising drug-free strategy for cancer post-operative management. Utilizing this Mn2+-embedding and ROS-responsive delivery system, it regulates surgery-induced immune responses and promotes sustained anti-tumor responses, potentially increasing the effectiveness of surgical cancer treatments.
摘要：
原理：手术切除是实体瘤的主要治疗方法，但手术后肿瘤的高复发率和转移率提出了重大挑战。锰(Mn2+),已知通过激活cGAS-STING途径增强树突状细胞介导的癌症免疫治疗，在术后癌症管理方面具有潜力。然而,实现Mn2+的延长和局部递送以刺激免疫应答而没有全身毒性仍然是一个挑战。方法：我们开发了一种嵌入Mn2-果胶微球（MnP@DOP-Gel）的术后微环境响应型石斛多糖水凝胶。此水凝胶系统响应于ROS释放Mn2-果胶微球（MnP），和MnP在体外显示出双重作用:促进免疫原性细胞死亡和激活免疫细胞(树突状细胞和巨噬细胞)。在小鼠皮下和转移性黑色素瘤模型中评估MnP@DOP-Gel作为术后治疗的功效及其免疫激活的潜力，探讨其与抗PD1抗体的协同作用。结果:MnP@DOP-Gel表现出ROS响应性释放MnP,它可以通过诱导肿瘤细胞的免疫原性细胞死亡和激活树突状细胞和巨噬细胞来启动抗肿瘤免疫应答的级联反应来发挥双重作用。体内实验表明，植入的MnP@DOP-Gel可显着抑制残留肿瘤的生长和转移。此外，MnP@DOP-Gel和抗PD1抗体的组合在预防转移或外翻脑肿瘤生长方面显示出优异的治疗效力。结论：MnP@DOP-Gel代表了一种有希望的癌症术后无药治疗策略。利用这种Mn2+嵌入和ROS响应传输系统，它调节手术诱导的免疫反应，促进持续的抗肿瘤反应，有可能提高癌症手术治疗的有效性。
