Cheng Zhuo, Xue Chencheng, Liu Minghan, Cheng Zhiming, Tian Gan, Li Menghuan, Xue Rui, Yao Xuemei, Zhang Yuan, Luo Zhong
School of Life Science, Chongqing University, Chongqing 400044, PR China; Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing 401329, PR China.
School of Life Science, Chongqing University, Chongqing 400044, PR China.
Acta Biomater. 2023 Oct 1;169:289-305. doi: 10.1016/j.actbio.2023.08.002. Epub 2023 Aug 5.
Immunotherapy is an emerging antitumor modality with high specificity and persistence, but its application for resected tumor treatment is impeded by the low availability of tumor-specific antigens and strong immunosuppression in the wound margin. Here a nanoengineered hydrogel is developed for eliciting robust cooperative ferroptosis-immunotherapeutic effect on resected tumors. Specifically, β-cyclodextrin (β-CD) is first grafted onto oxidized sodium alginate (OSA) through Schiff base ligation, which could trap cRGD-modified redox-responsive Withaferin prodrugs (WA-cRGD) to obtain the hydrogel building blocks (Gel@WA-cRGD). Under Ca-mediated crosslinking, Gel@WA-cRGD rapidly forms physiologically stable hydrogels, of which the porous network is used to deliver programmed cell death ligand 1 antibodies (aPD-L1). After injection into the post-surgical wound cavity, the β-CD-entrapped WA-cRGD is detached by the local acidity and specifically internalized by residual tumor cells to trigger ferroptosis, thus releasing abundant damage-associated molecular patterns (DAMPs) and tumor-derived antigens for activating the antigen-presenting cell-mediated cross-presentation and downstream cytotoxic T cell (CTL)-mediated antitumor responses. Furthermore, aPD-L1 could block PD-1/PD-L1 interaction and enhance the effector function of CTLs to overcome tumor cell-mediated immunosuppression. This cooperative hydrogel-based antitumor strategy for ferroptosis-immunotherapy may serve as a generally-applicable approach for postoperative tumor management. STATEMENT OF SIGNIFICANCE: To overcome the immunosuppressive microenvironment in resected solid tumors for enhanced patient survival, here we report a nanoengineered hydrogel incorporated supramolecular redox-activatable Withaferin prodrug and PD-L1 antibody, which could elicit robust cooperative ferroptosis-immunotherapeutic effect against residual tumor cells in the surgical bed to prevent tumor relapse, thus offering a generally-applicable approach for postoperative tumor management.
免疫疗法是一种新兴的具有高特异性和持久性的抗肿瘤方式，但其在切除肿瘤治疗中的应用受到肿瘤特异性抗原可用性低以及伤口边缘强烈免疫抑制的阻碍。在此，开发了一种纳米工程水凝胶，用于对切除的肿瘤引发强大的协同铁死亡-免疫治疗效果。具体而言，首先通过席夫碱连接将β-环糊精（β-CD）接枝到氧化海藻酸钠（OSA）上，其可捕获cRGD修饰的氧化还原响应性白英前药（WA-cRGD）以获得水凝胶构建块（Gel@WA-cRGD）。在钙介导的交联作用下，Gel@WA-cRGD迅速形成生理稳定的水凝胶，其多孔网络用于递送程序性细胞死亡配体1抗体（aPD-L1）。注射到手术后的伤口腔内后，被β-CD包裹的WA-cRGD被局部酸性环境解离，并被残留肿瘤细胞特异性内化以触发铁死亡，从而释放大量损伤相关分子模式（DAMPs）和肿瘤衍生抗原，以激活抗原呈递细胞介导的交叉呈递和下游细胞毒性T细胞（CTL）介导的抗肿瘤反应。此外，aPD-L1可阻断PD-1/PD-L1相互作用并增强CTL的效应功能，以克服肿瘤细胞介导的免疫抑制。这种基于协同水凝胶的铁死亡-免疫治疗抗肿瘤策略可作为术后肿瘤管理的一种普遍适用方法。意义声明：为克服切除实体瘤中的免疫抑制微环境以提高患者生存率，我们在此报告一种纳米工程水凝胶，其包含超分子氧化还原可激活的白英前药和PD-L1抗体，可对手术床中的残留肿瘤细胞引发强大的协同铁死亡-免疫治疗效果，以防止肿瘤复发，从而为术后肿瘤管理提供一种普遍适用的方法。
