β-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 β-elemene promotes M1 polarization of tumor-associated macrophages (TAMs) and enhances the efficacy of PD-L1 antibody (aPD-L1) in C57BL/6 mice. RNA sequencing and surface plasmon resonance revealed that β-elemene directly binds to FLT1 and inhibits the PI3K/AKT/FOXO1 signaling pathway, thereby mediating TAMs M1 polarization. Using Flt1 knockout mice, we further validated the critical role of Flt1 in TAMs polarization and confirmed that M1 polarization synergizes with aPD-L1 treatment. Furthermore, co-immunoprecipitation showed that the FLT1 intracellular domain binds to and phosphorylates the p85α subunit, triggering downstream signaling cascades. These findings elucidate the synergistic mechanism between β-elemene and aPD-L1. Moreover, given the clinical availability of both agents, they provide a strong rationale for further clinical evaluation of this combination therapy.