Nanodrug shows spatiotemporally controlled release of anti-PD-L1 antibody and STING agonist to effectively inhibit tumor progression after radiofrequency ablation

Abstract

The PD-1/PD-L1 blockade failed to prolong the progression-free survival of patients after radiofrequency ablation (RFA) treatment of liver metastases from colorectal cancers. We found that the PD-1/PD-L1 immune checkpoint blockade (ICB) therapy after RFA in mice model only had a temporary inhibition of tumor progression due to the limited number of mature dendritic cells (DCs) and the insufficient tumor infiltration/activation of cytotoxic T lymphocytes (CTLs). Our study further revealed that the activation of stimulator of interferon gene (STING) affecting tumor-infiltrating DCs and CD8+ T cells was only transient after RFA of tumor. Therefore, a nanovesicle capable of releasing the anti-PD-L1 antibody (αPD-L1) and STING agonist inside tumor in a spatiotemporally controlled manner was developed to evoke a robust anti-cancer immune response and immune memory for a long-term inhibition of tumor progression after RFA. The nanovesicle entrapping the hydrophilic STING agonist 5,6-dimethylxanthenone-4-acetate sodium salt (DMXAAst) in its lumen and anchoring αPD-L1 via an MMP-2-sensitive peptide linker was coated with PEG layer sheddable in acidic tumor microenvironment. The nanodrug design allowed the PEG coating to block off-target interaction between αPD-L1 and PD-L1-positive normal cells in blood and normal tissues, thereby reducing the immune-related adverse effects (irAEs). APD-L1 was firstly released in response to MMP-2 overexpressed in tumor tissue for ICB therapy, which promote the intracellular delivery of DMXAAst to activate STING in DCs. The synergistic effect of αPD-L1, DMXAAst and RFA evoked a robust anti-tumor immunity and long-term immune memory for a potent cancer therapy.