Reverse immune suppressive microenvironment in tumor draining lymph nodes to enhance anti-PD1 immunotherapy via nanovaccine complexed microneedle

The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-programmed death-1(anti-PD1)checkpoint blockade for immunotherapy,the efficacy of PD1/PD-L1 therapy deserves to be improved.Here,we constructed a novel transfersomes based nanovaccine complexed microneedles to enhance anti-PD1 immunotherapy via transdermal immunization for skin tumor therapy.Transfersomes were functionalized with DCs targeting moietyαCD40,co-encapsulated with antigens and adjuvant poly I:C.Moreover,transdermal administration promoted accumulation in tumor-draining lymph nodes(tdLN),which could facilitate cellular uptake,activate DCs maturation and enhance Th1 immune responses.Using a mouse melanoma model,combined therapy of such nanovaccine complexed microneedles with pembrolizumab(αPD1)was able to enhance cytotoxic T lymphocytes activation,promote infiltration and reduce regulatory T cells frequency in tdLN and tumor tissues,which achieved reversion of the immunosuppressive microenvironment into immune activation.This study highlighted the potential of transfersomes based nanovaccines complexed microneedles as an attractive platform for tumor immunotherapy.