IDO1 inhibition enhances CLDN18.2-CAR-T cell therapy in gastrointestinal cancers by overcoming kynurenine-mediated metabolic suppression in the tumor microenvironment.

ABSTRACT:

Background

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies but faces significant limitations in gastrointestinal tumors due to the immunosuppressive tumor microenvironment (TME). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the TME, suppresses T cell efficacy by catalyzing tryptophan degradation to kynurenine (Kyn), leading to T cell exhaustion and reduced cytotoxicity. This study investigates the role of IDO1 inhibition in overcoming metabolic suppression by kynurenine and enhancing Claudin18.2 (CLDN18.2) CAR-T cell therapy in gastric and pancreatic adenocarcinoma models.

Methods

We evaluated the impact of genetic knockdown and pharmacological inhibition of IDO1 (using epacadostat) on CAR-T cell functionali

SUBMITTER: Wu Z 

PROVIDER: S-EPMC11884131 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature