ß-Elemene Enhances the Efficacy of PD-L1 Inhibitor in Lung Cancer by Reprogramming Tumor-Associated Macrophages to M1 Phenotype via Suppressing FLT1/PI3K/AKT Signaling

Immune checkpoint inhibitors (ICI), epitomized by PD-1/PD-L1 antibodies, have ushered in a new era in lung cancer treatment. However, ICI monotherapy is only applicable to a small subset of patients with high PD-L1 expression, while most patients with low expression require combination therapies. In this study, we found that ß-elemene promotes M1 polarization of tumor-associated macrophages (TAM) and enhances the efficacy of PD-L1 antibody (aPD-L1) in C57BL/6 mice. RNA sequencing and surface plasmon resonance revealed that ß-elemene directly binds to FLT1 and inhibits the PI3K/AKT/FOXO1 signaling pathway, thereby mediating TAM M1 polarization. Using FLT1 knockout mice, we further validated the critical role of FLT1 in TAM polarization and confirmed that M1 polarization synergizes with aPD-L1 treatment. Furthermore, co-immunoprecipitation demonstrated that the intracellular domain of FLT1 interacts with and phosphorylates the p85a subunit, initiating downstream signaling cascades. These findings elucidate the synergistic mechanism between ß-elemene and aPD-L1. Importantly, as both agents are already clinically approved, we plan to conduct a clinical trial to evaluate the efficacy and safety of this combination therapy. Overall design: We performed RNA-seq on bone marrow-derived macrophages (BMDM) after their co-culture with LLC cells and subsequent treatment with either 100 µg/mL ß-elemene or PBS for 24 hours.