# Enhanced anti-liver tumor efficacy of chimeric antigen receptor-T cells via SATB1 modulation

## TL;DR

Modifying SATB1 in CAR-T cells improves their effectiveness against liver tumors by reducing exhaustion and boosting memory and cytotoxic functions.

## Contribution

The study identifies SATB1 as a novel modulator that simultaneously targets T-cell exhaustion and memory differentiation in CAR-T cells.

## Key findings

- SATB1 overexpression reduces inhibitory receptor expression and promotes a central memory phenotype in CAR-T cells.
- SATB1-engineered CAR-T cells show enhanced tumor control and survival in a hepatocellular carcinoma model.
- SATB1 reduces exhaustion markers in tumor-infiltrating T cells, improving CAR-T cell function.

## Abstract

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.