In situ MUC1-specific CAR engineering of tumor-supportive macrophages stimulates tumoricidal immunity against pancreatic adenocarcinoma

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized intervention strategies for various primary malignancies. However, the implementation of this approach in solid tumors, including fatal gastrointestinal cancer pancreatic adenocarcinoma (PAAD), is limited. Given the endogenous functions of macrophages and their extensive infiltration in the solid tumor microenvironment (TME), liposomalized nanoporters (LNPs) are constructed for in situ genetic engineering of intratumoral macrophages with a mucin 1-specific CAR, which redirect the phagocytic activity of these cells to target cancerous PAAD cells and subsequently prime locoregional anti-PAAD immunity. When systemically administered, any LNPs that escape clearance by the reticuloendothelial system become passively enriched in tumor tissues and unshell upon triggering with legumain intratumorally. The liberated nanoporters in turn introduce the CAR gene into the nucleus of macrophages, thereby locoregionally yielding PAAD-targeted CAR macrophages, which significantly enhances the antigen-specific phagocytosis by macrophages, elevates the antigen presentation specificity, and serially boosts the population of cytotoxic T lymphocytes, thus reducing the tumor burden and prolonging survival in PAAD mouse models. Our technology provides a practical antitumor immunotherapy for PAAD patients and may be broadly applicable for patients suffering from other solid malignancies that dually overexpress mucin 1 and legumain.