Miao Fenglin, Wang Zhao, Wang Qing, Zhou Changsheng, Zhou Xiao, Zheng Jialiang, Ma Yuan, Lin Zhenhang, Gao Yilai, Wu Ting, Zhang Yong, Gao Jing, Li Wengang
Cancer Research Center, School of Medicine, Xiamen University, Xiamen, 361102, China.
Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250014, China.
Mater Today Bio. 2025 Apr 26;32:101802. doi: 10.1016/j.mtbio.2025.101802. eCollection 2025 Jun.
Fibrosarcoma is a kind of highly malignant sarcoma with high recurrence rate after surgery and unsatisfying efficacy of radiotherapy and chemotherapy. Increasing the concentration of gasdermin in tumor cell to induce pyroptosis is a promising strategy to treat fibrosarcoma. However, the poor cytotoxic T lymphocytes (CTL) infiltration in tumor area limits the therapeutic effect with disabled positive feedback between pyroptosis and anti-tumor immunity. Induing tumor immunogenic cell death to activate anti-tumor immune and delivering gasdermin E (GSDME) to enhance tumor pyroptosis will rebuild the positive feedback. Hence, we proposed and constructed a genetically engineered GSDME vesicle coated nanoparticle (HV-FI) to achieve effective treatment of fibrosarcoma. First, the GSDME membrane-expressing tumor cells are constructed and the GSDME-displaying vesicles are extracted. Then the HV-FI is prepared by hybridizing red blood cell membranes and encapsulating ICG-loaded mesoporous FeO nanoparticles. The GSDME proteins on the vesicles can effectively induce fibrosarcoma cell pyroptosis with granzyme B. After NIR irradiation, fibrosarcoma cells released DAMPs and activated dendritic cells . In animal experiments, fibrosarcoma cells underwent pyroptosis and CTL infiltration was boosted in tumor microenvironment. That subsequently enhanced tumor cell pyroptosis with delivered GSDME, creating a synergetic effect of tumor cell pyroptosis and anti-tumor immune activation, ultimately leading to effective tumor clearance. Meanwhile, the immunological memory is established, preventing tumor recurrence after treatment. This work proposes and validates the applicability and effectiveness of nanotherapy based on enhanced tumor pyroptosis induction and immune activation, providing a new method for the treatment of unresectable fibrosarcoma.
纤维肉瘤是一种高度恶性的肉瘤，术后复发率高，放化疗效果不理想。提高肿瘤细胞中gasdermin的浓度以诱导细胞焦亡是治疗纤维肉瘤的一种有前景的策略。然而，肿瘤区域细胞毒性T淋巴细胞（CTL）浸润不足限制了治疗效果，因为细胞焦亡与抗肿瘤免疫之间的正反馈被破坏。诱导肿瘤免疫原性细胞死亡以激活抗肿瘤免疫并递送gasdermin E（GSDME）以增强肿瘤细胞焦亡将重建正反馈。因此，我们提出并构建了一种基因工程化的GSDME囊泡包被纳米颗粒（HV-FI）以实现对纤维肉瘤的有效治疗。首先，构建表达GSDME膜的肿瘤细胞并提取展示GSDME的囊泡。然后通过杂交红细胞膜并封装负载ICG的介孔FeO纳米颗粒制备HV-FI。囊泡上的GSDME蛋白可通过颗粒酶B有效诱导纤维肉瘤细胞焦亡。近红外照射后，纤维肉瘤细胞释放损伤相关分子模式并激活树突状细胞。在动物实验中，纤维肉瘤细胞发生焦亡，肿瘤微环境中CTL浸润增加。随后通过递送GSDME增强肿瘤细胞焦亡，产生肿瘤细胞焦亡与抗肿瘤免疫激活的协同效应，最终实现有效的肿瘤清除。同时，建立免疫记忆，防止治疗后肿瘤复发。这项工作提出并验证了基于增强肿瘤细胞焦亡诱导和免疫激活的纳米治疗的适用性和有效性，为不可切除纤维肉瘤的治疗提供了一种新方法。
