Tanshinone IIA restores CD8+ T-cell immunity in TNBC by suppressing the IDO1-kynurenine axis.

INTRODUCTION

Immune checkpoint blockade (ICB) benefits only a minority of patients with triple-negative breast cancer (TNBC), partly because tryptophan catabolism through indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) generates kynurenine, activates aryl hydrocarbon receptor (AhR) signaling, and suppresses CD8+ T-cell function. We investigated whether tanshinone IIA (Tan-IIA) modulates this pathway.

METHODS

We integrated network pharmacology with TCGA Breast Invasive Carcinoma transcriptomic analyses and evaluated Tan-IIA in 4T1 and MDA-MB-231 cells, tumor-conditioned-medium CD8+ T-cell assays, kynurenine add-back and IDO1-overexpression rescue experiments, and syngeneic 4T1 and EMT6 tumor models.

RESULTS

IDO1 and TDO2 were identified as upregulated Tan-IIA-associated candidates linked to an inflamed-yet-dysfunctional immune phenotype. Tan-IIA dose-dependently suppressed basal and IFN-γ-induced IDO1 and TDO2 expression, reduced the Kyn/Trp ratio and IDO activity, downregulated AhR target genes in CD8+ T cells, and restored CD8+ T-cell proliferation and effector-marker expression. Exogenous kynurenine and Ido1 overexpression substantially reversed these effects. In vivo, Tan-IIA reduced tumor growth, lowered tumor IDO1 and TDO2 expression, enhanced T-cell infiltration, and showed CD8-dependent antitumor activity. In checkpoint-resistant 4T1 tumors, Tan-IIA combined with anti-PD-1 produced the strongest tumor control and longest survival.

DISCUSSION: Tan-IIA relieves IDO1/TDO2-kynurenine-AhR metabolic immunosuppression and sensitizes TNBC to checkpoint blockade, supporting its further evaluation as a microenvironment-remodeling partner for ICB-resistant TNBC.