A Tumor‐Penetrating Nanomedicine Improves the Chemoimmunotherapy of Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a low survival rate. The therapeutic effect of chemotherapy and immunotherapy for PDAC is disappointing due to the presence of dense tumor stroma and immunosuppressive cells in the tumor microenvironment (TME). Herein, a tumor‐penetrating nanoparticle is reported to modulate the deep microenvironment of PDAC for improved chemoimmunotherapy. The tumor pH‐sensitive polymer is synthesized by conjugating N,N ‐dipentylethyl moieties and monomethoxylpoly(ethylene glycol) onto PAMAM dendrimer, into whose cavity a hydrophobic gemcitabine (Gem) prodrug is accommodated. They self‐assemble into nanoparticles (denoted as SPN@Pro‐Gem) with the size around 120 nm at neutral pH, but switch into small particles (≈8 nm) at tumor site to facilitate deep delivery of Gem into the tumor parenchyma. In addition to killing cancer cells that resided deeply in the tumor tissue, SPN@Pro‐Gem could modulate the TME by reducing the abundance of tumor‐associated macrophages and myeloid‐derived suppressor cells as well as upregulating the expression level of PD‐L1 of tumor cells. This collectively facilitates the infiltration of cytotoxic T cells into the tumors and renders checkpoint inhibitors more effective in previously unresponsive PDAC models. This study reveals a promising strategy for improving the chemoimmunotherapy of pancreatic cancer.