Dual Therapeutic Impact of AXL Inhibitor AB-329: Chemotherapy Sensitization and Immune Microenvironment Reprogramming in TNBC

AXL, a receptor tyrosine kinase, has emerged as a promising therapeutic target in triple-negative breast cancer (TNBC) due to its critical roles in tumor progression, metastasis, and immune evasion. In this study, we investigated the antitumor efficacy and immunomodulatory potential of AB-329, a selective AXL kinase inhibitor, in preclinical models of TNBC. Transcriptome analysis and single-cell RNA sequencing datasets revealed elevated AXL expression in mesenchymal TNBC subtypes and a negative association with immune cell infiltration. While AB-329 demonstrated moderate antiproliferative effects as a monotherapy, its combination with paclitaxel led to substantially enhanced antiproliferative and anti-metastatic effects compared to gemcitabine, DXd, and SN-38. In murine TNBC allograft models, the combination of AB-329 and paclitaxel significantly reduced tumor growth, and AB-329 increased activated natural killer (NK) cell infiltration in humanized mouse models. Analysis of human breast cancer tissue further confirmed that low AXL expression is associated with a higher presence of NK cells in the tumor. These findings suggest that AB-329 not only augments chemotherapy efficacy but also reshapes the tumor immune microenvironment, supporting its further development as a dual-action therapeutic strategy for AXL-positive TNBC.