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(+) 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.