LAUSR

Glioma treatment using targeted chemotherapy is still far from satisfactory due to not only the limited accumulation but also the multiple survival mechanisms of glioma cells, including up-regulation of both autophagy and programmed cell death ligand 1 (PD-L1) expression. Herein, we proposed a combined therapeutic regimen based on functional gold nanoparticles (AuNPs)-enabled chemotherapy, autophagy inhibition and blockade of PD-L1 immune checkpoint. Specifically, the legumain-responsive AuNPs (D&H-A-A&C) could be passively delivered to glioma site and form in situ aggregates in response to legumain, leading to enhanced accumulation of doxorubicin (DOX) and hydroxychloroquine (HCQ) at glioma site. HCQ could inhibit the DOX-induced cytoprotective autophagy and thus re-sensitize glioma cells to DOX. Moreover, inhibiting autophagy could also inhibit the formation of autophagy-related vasculogenic mimicry (VM) by glioma stem cells. In vivo studies demonstrated that D&H-A-A&C possessed promising anti-glioma effect. Moreover, co-treatment with anti-PD-L1 antibody was able to neutralize immunosuppressed glioma microenvironment and thus unleash anti-tumor immune response. In vivo studies showed D&H-A-A&C plus anti-PD-L1 antibody could further enhance anti-glioma effect and efficiently prevent recurrence. The effectiveness of this strategy presents a potential avenue to develop a more effective and more personalized combination therapeutic regimen for glioma patients. KEYWORDS: Combination therapy, autophagy inhibition, immune checkpoint, legumain responsive, glioma.