Reigniting the cancer-immunity cycle with nanoparticles for simultaneous delivery of oncolytic peptides and a TLR agonist

Immunotherapy using immune checkpoint inhibitors (ICIs) has emerged as one of the most potent cancer therapies. However, low response rates to ICI therapeutics, particularly in solid tumors, have been observed in clinical practice because of several factors, with the poor immunogenic condition of the tumor microenvironment (TME) being considered a key feature. In this study, we flamed up the TME of solid tumors by using LTX-315 (LTX), a first-in-class oncolytic cationic peptide, and an RNA drug, poly(I:C) (IC), Toll-like receptor (TLR) 3 agonist, to boost the therapeutic effect of anti-PD-1 (aPD1) therapy. Intelligent hybrid nanoparticles (NPs) were designed and fabricated with the decoration of CD47 mimicking peptide (CD47p) (LTX/IC-NP@CD47p) on their surfaces to suppress phagocytosis of phagocytes and enhance the persistence of NPs in the circulatory system, followed by improved accumulation in tumor tissue and a higher cellular uptake capacity of cancer cells. The results demonstrated that LTX/IC-NP@CD47p effectively triggered immunogenic cell death (ICD) in vitro and in vivo characterized by abundant damage-associated molecular pattern (DAMP) levels and robustly induced type I interferon release, which enhanced the immune condition of solid tumors with increased antitumor effector immune cells, supporting the therapeutic effect of aPD1 therapy. Moreover, the combination of LTX/IC-NP@CD47p treatment and aPD1 therapy inhibited tumor metastasis by reducing the epithelial-mesenchymal transition (EMT) in primary tumors, which prolonged the survival rate of tumor-bearing mice in the in vivo model. Thus, our study suggests a potent strategy for improving therapeutic efficacy of ICIs by combining an ICD inducer and TLR agonist to induce a highly immunogenic TME.