Zhao Zheng, Huang Yingbin, Wang Jing, Lin Hongsheng, Cao Fei, Li Shuxin, Li Yin, Li Ziqian, Liu Xuekui
State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China.
Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
Biomater Sci. 2023 Mar 14;11(6):2200-2210. doi: 10.1039/d2bm02026b.
While immunotherapy has emerged as a promising strategy to treat melanoma, the limited availability of immunotherapeutic agents in tumors due to the immunosuppressive tumor microenvironment dampens its efficacy. Pyroptosis is a gasdermin-mediated programmed necrosis that triggers the inflammatory tumor microenvironment and enhances the efficacy of tumor immunotherapy. Here, we prove that the CXCR4 antagonist T22 peptide specially targeted and became internalized into CXCR4 melanoma cells. Then we report a self-assembling nanotoxin that can be used to spatiotemporally target CXCR4-expression melanoma cells and enable tunable cellular pyroptosis. Specific activation of caspase 3 signal transduction triggers gasdermin-E-mediated pyroptosis. This nanotoxin induces pyroptotic cell death resulting in enhanced antitumor efficacy and minimized systemic side effects toward melanoma . This study offers new insights into how to engineer nanotoxins with tunable pyroptosis activity through specifically targeting CXCR4 for biomedical applications.
虽然免疫疗法已成为治疗黑色素瘤的一种有前景的策略，但由于免疫抑制性肿瘤微环境导致肿瘤中免疫治疗药物的可用性有限，降低了其疗效。细胞焦亡是一种由gasdermin介导的程序性坏死，可触发炎性肿瘤微环境并增强肿瘤免疫治疗的疗效。在此，我们证明CXCR4拮抗剂T22肽可特异性靶向并内化进入CXCR4黑色素瘤细胞。然后我们报告了一种自组装纳米毒素，可用于时空靶向CXCR4表达的黑色素瘤细胞并实现可控的细胞焦亡。半胱天冬酶3信号转导的特异性激活触发gasdermin-E介导的细胞焦亡。这种纳米毒素诱导焦亡性细胞死亡，从而增强抗肿瘤疗效并使对黑色素瘤的全身副作用最小化。本研究为如何通过特异性靶向CXCR4设计具有可控细胞焦亡活性的纳米毒素用于生物医学应用提供了新见解。
