Reversal of tumour immune evasion via enhanced MHC-Class-I antigen presentation by a dual-functional RNA regulated system

作者：Chaoyang Meng, Huipeng Zhang, Xuewen Yi, Gangcheng Kong, Xiaoge Zhang, Bei Wang, Yan Xu, Haoxiang Qi, Qing Wu, Ke Zhang, Jiaying Cao, Xiaohan Lin, Huiheng Feng, Jianxiang Chen, Shusen Zheng, Zhen Gu, Hongjun Li, Ling Qi · 发表于：Molecular Cancer · 年份：2025 · DOI：10.1186/s12943-025-02480-x · 被引用次数：13 · 研究领域：CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

Motivating the immune system to target tumour cells plays an increasingly prominent role in the treatment of hepatocellular carcinoma (HCC), but challenges such as low overall response rates persist in current clinical practice. Tumour cell MHC-Class-I (MHC-I) downregulation and antigen loss are typical mechanisms of immune evasion. To this end, a dual-functional RNA-based strategy was conceived for HCC immunotherapy. MHC-I expression on HCC and paratumour tissues from patients was assessed, and the correlations between MHC-I regulators and HCC prognosis were analyzed. Small interfering RNA (siRNA) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and mRNA encoding tumour antigens were encapsulated in a fluorinated lipid nanoparticle (LNP), which direct nucleic acids primarily to the liver, making it ideal for HCC treatment. Anti-tumour efficacy was investigated in an orthotopic HCC model, with single-cell RNA sequencing used for in-depth analysis of the tumour microenvironment (TME). A marked downregulation of MHC-I expression was observed in HCC tumour cells from a cohort of patients, with this MHC-I suppression correlating with poor prognosis and diminished responsiveness to immunotherapy. Among the various MHC-I regulators, PCSK9 is the only one that shows a significant correlation with the prognosis of HCC patients. Knockdown of PCSK9 inhibited MHC-I degradation and thus increased the efficiency of antigen presentation by up to sixfold compared to untreated...