CRISPR/Cas9-mediated SHP-1-knockout T cells combined with simvastatin enhances anti-tumor activity in humanized-PDX HCC model

作者：Huaping Liu, Wu Ge, Xiaoping Yu, Jianwei Luo, Juan Zhang, Min Yang, Lu Cao, Yangnan Zhang, Ruike Wang, Cejun Yang, Pei Li, Mengyu Tian, Peng Xu, Lei Peng, Di Wu, Muqi Liu, Qi Liang, Shengwang Zhang, Wei Li, Pengfei Rong, Hailan Li, Xiaoqian Ma, Wei Wang · 发表于：iScience · 年份：2025 · DOI：10.1016/j.isci.2025.112266 · 被引用次数：7 · 研究领域：CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers、Phagocytosis and Immune Regulation

Hepatocellular carcinoma (HCC) resists immunotherapy due to its immunosuppressive microenvironment. Sarcoma homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) inhibits T cell receptor signaling, and its pharmacological inhibition is limited by poor selectivity and membrane permeability. Here, we generated CRISPR-edited SHP-1-knockout (KO) CD8 + T cells to enhance adoptive therapy against HCC. Single-cell RNA sequencing of HCC patient T cells revealed elevated SHP-1 in exhausted subsets. SHP-1-KO T cells exhibited increased effector memory T cells (TEM) proportions and enhanced IFN-γ/Granzyme B/perforin secretion, improving cytotoxicity against HCC lines. In humanized PDX models, SHP-1-KO T cells demonstrated superior tumor-killing activity. Transcriptomics identified upregulated lipid metabolism pathways, with HMGCR as a hub gene. Combining SHP-1-KO T cells with simvastatin (HMGCR inhibitor) synergistically amplified anti-HCC efficacy. This study proposes a dual strategy combining SHP-1-targeted cell therapy and metabolic modulation to overcome immunotherapy resistance, offering a translatable approach for HCC treatment.