Abstract
The presence of multiple immunosuppressive targets and insufficient activation and infiltration of cytotoxic T lymphocytes (CTLs) allow tumor cells to escape immune surveillance and disable anti-PD-1/PD-L1 immunotherapy. Nanobiotechnology-engineered autologous tumor vaccines (ATVs) that were camouflaged by tumor cell membrane (TCM) were designed to activate and facilitate CTLs infiltration for killing the unprotected lung tumor cells, consequently realizing the sequential immunotherapy. PDE5 was firstly screened out as a new immunosuppressive target of lung cancer in clinical practice. Immediately afterwards, phosphodiesterase-5 (PDE5) and programmed cell death 1 ligand 1 (PD-L1) dual-target co-inhibition was proposed to unfreeze the immunosuppressive microenvironment of NSCLC. Systematic studies validated that this ATVs-unlocked sequential immunotherapy after co-encapsulating PDE5 inhibitor and NO donor (i.e., l-arginine) exerted robust anti-tumor effects through increasing inducible nitric oxide synthase (iNOS) expression, blockading PDE5 pathway and activating systematic immune responses, which synergistically eradicated local and abscopal lung cancers in either orthotopic or subcutaneous models. The pluripotent ATVs that enable PDE5 inhibition and sequential immunotherapy provide a new avenue to mitigate immunosuppressive microenvironment and magnify anti-PD-1/PD-L1 immunotherapy.