{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:26:06Z","timestamp":1792106766382,"version":"4.4.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The exhaustion of chimeric antigen receptor T cells (CAR-T) hampers the efficacy of CAR-T cell therapy. Persistent antigen stimulation in T cells results in a surge of intracellular reactive oxygen species (ROS). ROS, as mitochondrial metabolites, alter the integrity of the mitochondrial membrane and promote T-cell exhaustion. Glutathione <jats:italic>S<\/jats:italic>-transferase Pi-1 (GSTP1), a member of the glutathione <jats:italic>S<\/jats:italic>-transferase family, is an important enzyme in the intracellular clearance of ROS. Overexpression of GSTP1 may enhance the antitumor capability of CAR-T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The correlations between GSTP1 and genes related to T-cell exhaustion were analyzed using the TIMER database. Peripheral blood mononuclear cells (PBMCs) were collected from patients with hematologic malignancies (<jats:italic>n<\/jats:italic> =\u00a061) and healthy donors (<jats:italic>n<\/jats:italic> =\u00a045) to measure GSTP1, B-lymphocyte maturation protein 1 (BLIMP1), and programmed cell death protein 1 (PD-1) expression by qRT-PCR. A T-cell exhaustion model was established to assess GSTP1 expression by Western blotting. The dual-luciferase assay and ChIP-qPCR were used to determine whether the transcription factor BLIMP1 negatively regulated the activity of the GSTP1 promoter. CD19 CAR-T, GSTP1 overexpressing CAR-T (GSTP1 CAR-T), and GSTP1-knockdown CAR-T (shGSTP1 CAR-T) cells were generated to evaluate their antitumor capacity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>GSTP1 expression was downregulated when BLIMP1 and PD-1 were upregulated in PBMCs of cancer patients and in the <jats:italic>in vitro<\/jats:italic> T-cell exhaustion model. Meanwhile, ROS levels in the T-cell exhaustion model increased. Mechanistically, the BLIMP1 transcription factor negatively regulated the activity of the GSTP1 promoter. Based on these findings, we engineered GSTP1 CAR-T cells, which exhibited improved functionality. GSTP1 CAR-T cells increased the TEMRA population, enhanced proliferation and cytotoxicity, elevated antioxidant capacity, increased IL-2 and IFN-\u03b3 secretion, reduced the expression of immune checkpoints, and decreased apoptosis. <jats:italic>In vivo<\/jats:italic>, the residual levels of GSTP1 CAR-T cells were higher than those of Cluster of Differentiation 19 (CD19) CAR-T cells and shGSTP1 CAR-T cells, indicating that GSTP1 CAR-T cells exhibited a strong antitumor capacity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>BLIMP1 directly suppressed GSTP1 transcription, whereas GSTP1 overexpression enhanced the antitumor capacity of CAR-T cells and maintained redox homeostasis, providing a novel therapeutic strategy to improve CAR-T cell immunotherapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1665407","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T05:34:22Z","timestamp":1758864862000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["GSTP1 improves CAR-T cell proliferation and cytotoxicity to combat 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