CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma

CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma

Abstract 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,...

Full description

Saved in:
Bibliographic Details
Main Authors: Shuyao Zhang, Hong Jiang, Chengkuan Zhao, Yanli Lei, Shaojie Liu, Chengcheng Xu, Xiaoshan Chen, Danling Zheng, Xiaolong Wu, Xinyue Lin, Wang Chen, Yun Chen, Jianxiang Huang, XiaoLong Wei, Yihui Huang, Chaoxian Lin
Format: Article
Language:English
Published: BMC 2025-07-01
Series:Journal of Nanobiotechnology
Subjects:
Esophageal squamous cell carcinoma
Tumor microenvironment
Cancer-associated fibroblasts
CXCL12
SiRNA nanoparticles
Online Access:https://doi.org/10.1186/s12951-025-03476-x
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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. Graphical abstract
ISSN:1477-3155

Similar Items