The clinical outcomes of
cancer nanovaccine have been largely impeded owing to the low
antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment (TME). Here, we reported a
tumor acidity-responsive
nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes (TILs) using hybrid
micelles (HM), which encapsulated
colony stimulating factor 1 receptor (CSF1-R) inhibitor
BLZ-945 and
indoleamine 2,3-dioxygenase (IDO) inhibitor NLG-919 in its core and displayed a model
antigen ovalbumin (OVA) on its surface (denoted as BN@HM-OVA). The bioactive
nanovaccine is coated with a
polyethylene glycol (PEG) shell for extending nanoparticle circulation. The shell can be shed in response to the weakly acidic tumor microenvironment. The decrease in size and the increase in positive charge may cause the deep
tumor penetration of drugs. We demonstrated that the bioactive
nanovaccine dramatically enhance antigen presentation by dendritic cells (DCs) and drugs transportation into M1-like tumor-associated macrophages (TAMs) and
tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME. Such bioactive
nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment, leading to
tumor growth inhibition in prophylactic and therapeutic E.G7-OVA
tumor models. Furthermore, combining the bioactive
nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term
tumor inhibition, based on the optimal timing and sequence of PD-1 blockade against
T cell receptor. This research provides a new strategy for the development of efficient
cancer immunotherapy.