ST6GAL1 糖工程重编程细胞因子信号并在 Galectin-3 介导的免疫抑制下维持 CAR-T 细胞的代谢适应性

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, durable responses remain limited by tumor microenvironment (TME)-mediated immunosuppression. Galectin-3 (Gal-3), a -galactoside-binding lectin enriched in the TME, contributes to CAR-T cell dysfunction by impairing cytotoxicity, promoting apoptosis, and altering cellular signaling.

While we previously demonstrated that enforced expression of the 2,6 sialyltransferase ST6GAL1 reduces galectin binding and improves CAR-T cell function, the mechanistic basis underlying this protection remains unclear.

Here, we report that Gal-3 induced a hypometabolic state in CAR-T cells characterized by reduced mitochondrial function, ATP production, and glucose utilization. In contrast, ST6GAL1-overexpressing CAR-T cells preserved metabolic fitness and functional resilience under Gal-3 stress.

Additionally, Gal-3 rewired cytokine signaling by increasing IL-5 expression and dysregulating downstream pathways, whereas enforced ST6GAL1 expressing CAR-T cells exhibited increased SOCS1 and SOCS3 expression and attenuated STAT5 activation.

Transcriptomic analysis of CAR-T cells from diffuse large B-cell lymphoma patients further revealed enrichment of STAT5-associated signaling and SOCS1 expression in complete responders compared to partial responders. Collectively, these findings identify glycoengineering as a promising strategy to enhance CAR-T cell persistence and function under Gal-3-mediated immunosuppressive stress.