AID/HAT1 介导的 JAG1/NOTCH 信号表观遗传启动驱动 TNBC 肿瘤微环境重编程

Triple-negative breast cancer (TNBC) presents a formidable therapeutic challenge due to its aggressive behavior, molecular heterogeneity, and lack of actionable targets.

This study identifies activation-induced cytidine deaminase (AID) as a pivotal epigenetic driver reprogramming the tumor microenvironment (TME) via non-canonical regulation of NOTCH signaling.

Mechanistically, AID recruits histone acetyltransferase 1 (HAT1) to form a chromatin-remodeling complex that binds the JAG1 promoter region (-1. 5 kb to -1. 1 kb), inducing H4K5 acetylation and transcriptional activation. This AID/HAT1-JAG1 axis amplifies NOTCH signaling in TNBC models, and genetic ablation of either AID or JAG1 suppresses malignant progression.

Pharmacological disruption using 4-Deoxyuricine (AID antagonist) and MG149 (HAT1 inhibitor) reduces JAG1 acetylation, attenuates NOTCH signaling, and reshapes the TME by depleting AID/HAT1-JAG1 axis and enhancing the infiltration of T cells, NK cells, and B cells. Clinically, AID and JAG1 co-expression enhances immune cell infiltration in TME, which predicts poor survival in TNBC cohorts.

Our findings redefine AID's role beyond its function in mediating mutagenesis, positioning it as a master epigenetic regulator of TNBC plasticity through acetylation-dependent NOTCH activation. These results resolve the paradox of NOTCH inhibitor resistance by identifying JAG1's epigenetic priming as a prerequisite for ligand-receptor signaling. Targeting the AID/HAT1-JAG1 axis offers a dual therapeutic strategy to overcome TME-mediated therapy resistance and provides a blueprint for precision immunotherapy in AID-positive TNBC subgroups.