CRISPR/Cas9-mediated SHP-1-knockout T cells combined with simvastatin enhances anti-tumor activity in humanized-PDX HCC model
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<sup>+</sup> 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.
Authors
- Wei Wang (ORCID: https://orcid.org/0000-0002-3409-7846)
- Lu Cao (ORCID: https://orcid.org/0000-0001-6644-0963)
- Peng Xu (ORCID: https://orcid.org/0000-0001-9061-2841)
- Muqi Liu (ORCID: https://orcid.org/0009-0007-7631-2798)
- Lei Peng (ORCID: https://orcid.org/0000-0003-2932-8504)
- Hailan Li (ORCID: https://orcid.org/0000-0001-9980-6896)
- Yangnan Zhang (ORCID: https://orcid.org/0000-0003-2399-0636)
- Xiaoping Yu
- Shengwang Zhang
- Mengyu Tian (ORCID: https://orcid.org/0000-0003-2289-4415)
- Ruike Wang (ORCID: https://orcid.org/0009-0004-9947-6304)
- Pengfei Rong (ORCID: https://orcid.org/0000-0001-5473-1982)
- Di Wu (ORCID: https://orcid.org/0000-0001-5742-5091)
- Min Yang (ORCID: https://orcid.org/0000-0002-5321-7698)
- Wei Li (ORCID: https://orcid.org/0000-0001-7864-404X)
- Juan Zhang (ORCID: https://orcid.org/0009-0004-7771-798X)
- Pei Li (ORCID: https://orcid.org/0000-0002-1548-4218)
- Qi Liang (ORCID: https://orcid.org/0000-0002-0054-1478)
- Huaping Liu (ORCID: https://orcid.org/0000-0001-7017-4127)
- Jianwei Luo (ORCID: https://orcid.org/0009-0004-4777-6110)
- Xiaoqian Ma (ORCID: https://orcid.org/0000-0002-5798-8991)
- Cejun Yang
- Wu Ge
Institutions
- Central South University (CN)
- Hunan Normal University (CN)
- Hunan Cancer Hospital (CN)
- Xiangya Hospital Central South University (CN)
Publication Details
- Journal
- iScience
- Published
- 2025-03-22
- DOI
- https://doi.org/10.1016/j.isci.2025.112266
- Citations
- 4
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- National Natural Science Foundation of China
- Science and Technology Program of Hunan Province