Remodeling tumor immunosuppression with molecularly imprinted nanoparticles to enhance immunogenic cell death for cancer immunotherapy

Abstract

Insufficient tumor accumulation and distribution of immunogenic cell death (ICD) inducer as well as low antitumor immunity severely restrict the therapeutic efficacy of tumor immunotherapy. Tumor associated fibroblasts (TAFs) are important in tumor extracellular matrix (ECM) remodeling and immune evasion. Reprogramming tumor immunosuppressive microenvironment via TAFs regulation might present a promising way for enhanced ICD effect and complete tumor elimination. In this study, TAFs derived tryptase imprinted nanoparticles (DMSN@MIPs) are developed to modulate TAFs and improve tumor immunotherapy effect of doxorubicin liposomes (DOX/LIP). Tryptase (TPS), secreted by mast cells, are found to support tumor growth via transcriptionally activating TAFs to an activated state with increased expression of fibroblast activation marker α-smooth muscle actin (α-SMA). DMSN@MIPs canbe used as artificial antibodies, which effectively neutralize TPS, reduce TAFs activation, promote intra-tumor penetration of DOX/LIP and enhance ICD effect induced by DOX/LIP. In addition, the combined administration system remodels immunosuppressive microenvironment, which not only significantly up-regulates immune cells (DC cells, CD8+T cells, NK cells), but also significantly down-regulates immunosuppressive cells (Treg cells, MDSCs cells). Our results support the DMSN@MIPs canbe a promising approach to improve ICD efficacy in cancer immunotherapy.