Synergistic therapy for pancreatic cancer by deactivating cancer-associated fibroblasts and driving T-cell migration into tumor microenvironment using nanochaperone delivery system

The success of immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is greatly limited by the scarcity of cytotoxic T lymphocytes (CTLs) in tumor microenvironment, which is mainly due to the physical barrier formed by a dense extracellular matrix (ECM). Here we reported a potent strategy to rectify the CTLs infiltration in PDAC by synergistically deactivating cancer-associated fibroblasts (CAFs) and driving T-Cell migration into tumor microenvironment. This combination therapy is achieved by co-delivery of vitamin D receptor ligand (calcipotriol, Cal) and chemokine (CXCL9) using nanochaperone (nChap) delivery platform. We demonstrate that Cal reverses the activated CAFs to quiescence for resulting in a loosened ECM, while the CXCL9 gradient increases the recruitment signal of CD8⁺ T cells, synergistically enhancing the intratumoral infiltration of CD8⁺ T cells. Noteworthily, this system (Cal@nChap-CXCL9) promotes both the penetration of immunotherapeutic (anti-PD-1) and chemotherapeutic (gemcitabine), significantly enhancing the efficacy of chemo-immunotherapy for advanced large Panc02 tumors. This study provides a promising strategy for enhanced PDAC immunotherapy.