Zhang Shuyao, Jiang Hong, Zhao Chengkuan, Lei Yanli, Liu Shaojie, Xu Chengcheng, Chen Xiaoshan, Zheng Danling, Wu Xiaolong, Lin Xinyue, Chen Wang, Chen Yun, Huang Jianxiang, Wei XiaoLong, Huang Yihui, Lin Chaoxian
Department of Pharmacy, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People's Republic of China.
Department of Nursing, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, 510220, People's Republic of China.
J Nanobiotechnology. 2025 Jul 16;23(1):519. doi: 10.1186/s12951-025-03476-x.
Esophageal squamous cell carcinoma (ESCC) is associated with a highly immunosuppressive tumor microenvironment (TME), driven in part by cancer-associated fibroblasts (CAFs) that promote immune evasion through the secretion of CXCL12. CXCL12 interacts with the CXCR4 receptor on immune cells, disrupting CD8 T cell migration and anti-tumor function. To address this, we developed an innovative siRNA-based therapeutic approach targeting CXCL12 in CAFs. Using lipid nanocarriers (LNCs) as delivery vehicles, we engineered LNCs@si-CXCL12 nanoparticles to specifically silence CXCL12 expression in CAFs. In vitro studies demonstrated that LNCs@si-CXCL12 restored CD8 T cell migration and inhibited ESCC cell proliferation and migration. In vivo experiments in a spontaneous ESCC mouse model showed that CXCL12 silencing through nanoparticle delivery significantly reduced tumor growth, enhanced CD8 T cell-mediated tumoricidal activity, and improved overall survival. These findings highlight the potential of siRNA-loaded nanoparticles targeting CXCL12 as a novel therapeutic strategy to reprogram the immunosuppressive TME and enhance immune responses in ESCC. This approach provides a promising avenue for improving treatment outcomes and overcoming immune evasion in ESCC.
食管鳞状细胞癌（ESCC）与高度免疫抑制的肿瘤微环境（TME）相关，部分原因是癌症相关成纤维细胞（CAFs）通过分泌CXCL12促进免疫逃逸。CXCL12与免疫细胞上的CXCR4受体相互作用，破坏CD8 T细胞迁移和抗肿瘤功能。为了解决这个问题，我们开发了一种创新的基于小干扰RNA（siRNA）的治疗方法，靶向CAFs中的CXCL12。使用脂质纳米载体（LNCs）作为递送载体，我们构建了LNCs@si-CXCL12纳米颗粒，以特异性沉默CAFs中CXCL12的表达。体外研究表明，LNCs@si-CXCL12恢复了CD8 T细胞迁移，并抑制了ESCC细胞的增殖和迁移。在自发ESCC小鼠模型中的体内实验表明，通过纳米颗粒递送沉默CXCL12可显著降低肿瘤生长，增强CD8 T细胞介导的杀瘤活性，并改善总体生存率。这些发现突出了靶向CXCL12的载siRNA纳米颗粒作为一种新型治疗策略的潜力，该策略可重新编程免疫抑制性TME并增强ESCC中的免疫反应。这种方法为改善ESCC的治疗效果和克服免疫逃逸提供了一条有前景的途径。
