ARID5A 稳定吲哚胺 2, 3-双加氧酶表达并增强结直肠癌中 CAR-T 细胞耗竭

Resistance to chimeric antigen receptor (CAR) T-cell therapy remains a significant challenge in the treatment of solid tumors. This resistance is attributed to various factors, including antigen loss, immunosuppressive tumor microenvironment, and upregulated checkpoint molecules. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that promotes immune escape in tumors. In this study, we investigated the role of ARID5A (AT-rich interactive domain 5A) in resistance to CAR-T cell therapy.

Our findings revealed that ARID5A upregulation in tumor cells induces T cell exhaustion and immune evasion.

Mechanistically, ARID5A plays a crucial role in resistance to CAR-T cell therapy by stabilizing IDO1 mRNA, leading to upregulation of IDO1 expression. Elevated IDO1 expression facilitates the conversion of tryptophan to kynurenine, which contributes to CAR-T cell exhaustion.

Moreover, kynurenine accumulation within CAR-T cells activates the aryl hydrocarbon receptor (AhR), further exacerbating the exhaustion phenotype.

Importantly, we demonstrated that targeting the ARID5A-IDO1-AhR axis using AhR or IDO1 inhibitors effectively alleviated T cell exhaustion induced by ARID5A.

These findings suggest that modulating the ARID5A-IDO1-AhR axis may represent a promising therapeutic strategy to overcome CAR T-cell therapy resistance in solid tumors and enhance treatment efficacy.