Immunochemotherapeutic nanoparticles inhibit cancer-promoting fibroblasts subtypes for pancreatic ductal adenocarcinoma

Abstract

Cancer-associated fibroblasts (CAFs) and immunosuppressive microenvironment play important roles in the progression of pancreatic ductal adenocarcinoma (PDAC). Myofibroblast CAFs (myCAFs) and antigen-presenting CAFs (apCAFs) are cancer-promoting fibroblast (CPF) subtypes which could promote dense extracellular matrix (ECM) formation to inhibit drug penetration and induce the immunosuppressive microenvironment. The inhibition of CPF subtypes may help improve the PDAC treatment efficacy. Herein the engineered CPF-inhibiting nanoparticles are constructed with BSA-MnO₂-Niclosamide nanoparticles coated with exosomes encapsulating gemcitabine (BMN/GEM@PE) to substantially inhibit the progression and liver metastasis of PDAC by inhibiting the STAT3/p-STAT3 signals. The nanoparticles could significantly reduce the proportion of cancer-promoting CAF subtypes (myCAFs and apCAFs), which induce a shift from immune "cold" tumor to "hot" tumor phenotype. The reduced myCAFs by nanoparticles could promote the drug penetration and the infiltration of CD8⁺ T cells, and the decreased apCAFs lead to the decrease of the regulatory T cells. The new nanoparticles-based treatment strategies that the CAFs-subtypes modulation may influence the tumor immune microenvironment, which provide an opportunity to improve the immunochemotherapy for PDAC.