A Dendritic Cell‐Nanogel Conjugate for Tumor‐Draining Lymph Node‐Specific PD‐L1 Blockade

Abstract

Abstract Targeted blockade of immune checkpoints within tumor‐draining lymph nodes (TDLNs) represents a promising strategy to potentiate immune checkpoint blockade (ICB) therapy. However, the limited delivery of checkpoint inhibitors to TDLNs and inadequate T cell priming persist as major challenges. In this study, an innovative dendritic cell (DC)‐based strategy is developed for the targeted delivery of ICB antibodies to TDLNs. The platform is fabricated by conjugating anti‐PD‐L1 antibody nanogels with DCs, which are further enhanced by pre‐treating DCs with tumor antigens. Subcutaneous administration enabled DCs to execute their intrinsic TDLN‐tropic migration, thus facilitating antibody delivery and release under reductive conditions. The antigen‐loaded DCs mobilized T cell immunity, while the anti‐PD‐L1 antibodies block PD‐L1 on dendritic cells and myeloid cells within TDLNs, thereby augmenting systemic antitumor immunity. This approach significantly suppresses breast cancer growth, leading to 83.3% of treated mice being tumor‐free. This study presents a novel strategy for TDLN‐targeted PD‐L1 blockade by harnessing the intrinsic TDLN tropism of DCs, unveiling new translational opportunities of combining DC‐based vaccination with ICB therapy.