Modulating Electrophysiological Behavior of Dendritic Cells using Metal Ion-Chelated Phenylalanine Nanostructures for Cancer Immunotherapy

Immunosuppressive tumors microenvironment (TME) strongly influences response rates in patients receiving immune checkpoint blockade (ICB)-based cancer immunotherapies, such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1). Hence, therapeutic modalities aimed at reversing immunosuppressive TME should significantly improve PD-1/PD-L1-based immunotherapy. Here, we demonstrate that metal ion-chelated L-phenylalanine (L-Phe) nanostructures synergize with short-term starvation (STS) to remodel the immunosuppressive TME. Zinc ions, ferrous ions (Fe2+) and magnesium ions (Mg2+) are assembled with L-Phe to form nanosheets (Ph-Zn), nanoneedles (Ph-Fe) and nanospheres (Ph-Mg), respectively. Metal ion-chelated L-Phe nanostructures modulate the electrophysiological behaviors of dendritic cells (DCs) and activate them through NLRP3-inflammasome and calcium-mediated nuclear factor-kB pathway. Specifically, Ph-Zn nanosheets show the highest change in Kv1.3 current traces, thereby more effectively alleviating the immunosuppressive TME. We find that STS not only promote the cellular uptake of nanostructures through amino acid transporters, but also play a key role in DCs maturation and tumor-specific cytotoxic T lymphocytes (CTLs) responses. This study demonstrates the potential role of metal ion-chelated L-Phe nanostructures in activating immune responses and that STS treatment can be used to improve nanomaterials-mediated cancer immunotherapy.