Enhanced Anti-Liver Tumor Efficacy of Chimeric Antigen Receptor-T Cells via SATB1 Modulation

Although Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable success in treating hematopoietic malignancies, its clinical application in solid tumors is profoundly hindered by persistent T-cell exhaustion within the immunosuppressive tumor microenvironment (TME). Here, we identified SATB1—a genome organizer regulating chromatin architecture—as a key suppressor of CAR-T cell exhaustion. In Glypican-3 (GPC3)-targeted CAR-T cells, SATB1 was significantly downregulated in tumor-infiltrating exhausted populations. SATB1 overexpression not only reduced expression of multiple inhibitory receptors (PD-1, CTLA-4, TIM3 and LAG-3), but also promoted a central memory phenotype, enhancing cytokine production and cytotoxicity against hepatocellular carcinoma (HCC) cells in vitro . In vivo , SATB1-engineered CAR-T cells exhibited superior tumor control and promoted survival, accompanied by reduced exhaustion markers in tumor-infiltrating T cells. These functional improvements are consistent with the reported role of SATB1 in modulating T cell exhaustion, positioning it as a multifunctional enhancer of CAR-T cell fitness. Collectively, our study unveils SATB1 as a multifunctional modulator that simultaneously targets exhaustion and memory differentiation, offering a novel strategy to enhance CAR-T efficacy against solid tumors.