Sensitizing Tumors to Immune Checkpoint Blockage via STING Agonists Delivered by Tumor-Penetrating Neutrophil Cytopharmaceuticals

Abstract

Immune checkpoint inhibitors (ICIs) have displayed potential efficacy in triple-negative breast cancer (TNBC) treatment, while only a minority of patients benefit from ICI therapy currently. Although activation of the innate immune stimulator of interferon genes (STING) pathway potentiates antitumor immunity and thus sensitizes tumors to ICIs, the efficient tumor penetration of STING agonists remains critically challenging. Herein, we prepare a tumor-penetrating neotype neutrophil cytopharmaceutical (NEs@STING-Mal-NP) with liposomal STING agonists conjugating on the surface of neutrophils, which is different from the typical neutrophil cytopharmaceutical that loads drugs inside the neutrophils. We show NEs@STING-Mal-NP that inherit the merits of neutrophils including proactive tumor vascular extravasation and tissue penetration significantly boost the tumor penetration of STING agonists. Moreover, the backpacked liposomal STING agonists can be released in response to hyaluronidase rich in the tumor environment, leading to enhanced uptake by tumorinfiltrating immune cells and tumor cells. Thus, NEs@STING-Mal-NP effectively activate the STING pathway and reinvigorate the tumor environment through converting macrophages and neutrophils to antitumor phenotypes, promoting the maturation of dendritic cells, and enhancing the infiltration and tumoricidal ability of T cells. Specifically, this cytopharmaceutical displays a significant inhibition on tumor growth and prolongs the survival of TNBC-bearing mice when combined with ICIs. We demonstrate that neutrophils serve as promising vehicles for delivering STING agonists throughout solid tumors and the developed neutrophil cytopharmaceuticals with backpacked STING agonists exhibit huge potential in boosting the immunotherapy of ICIs.

Lipid‐based nanoparticles as drug delivery systems for cancer immunotherapy

“…In another study, tumor‐penetrating neutrophils cytopharmaceuticals with STING agonists were developed. In brief, they prepared a cationic liposomal STING agonists (DMXAA) coated with negative HA‐maleimide (HA‐Mal) and conjugated these onto the surface of neutrophils, named NEs@STING‐Mal‐NP 369 . The NEs@STING‐Mal‐NP has the ability of penetrating the tumor vascular endothelium and quick STING agonist release.…”

“…The NEs@STING‐Mal‐NP has the ability of penetrating the tumor vascular endothelium and quick STING agonist release. These characteristics endowed NEs@STING‐Mal‐NP with an increased absorption rate by immune cells and tumor cells, resulting in an antitumor TME stated via macrophages and neutrophils phenotype education and T cell infiltration improvement 369 …”

“…These characteristics endowed NEs@STING-Mal-NP with an increased absorption rate by immune cells and tumor cells, resulting in an antitumor TME stated via macrophages and neutrophils phenotype education and T cell infiltration improvement. 369…”

NIR-II fluorescence and PA imaging guided activation of STING pathway in photothermal therapy for boosting cancer immunotherapy by theranostic thermosensitive liposomes

“…22,23 However, the therapeutic effect of STING agonist is compromised owing to the rapid plasma clearance, poor membrane permeability, and low accumulation in the tumor. [24][25][26][27] Drug delivery systems (DDSs) based on nanotechnology present a great potential to intelligently control the release of drugs, which can protect the drug from premature degradation, optimize the pharmacokinetic profile and manipulate drug distribution in tissues. DDSs with smart drug carriers can release active ingredients at appropriate sites in response to certain physiological variables or external physicochemical stimuli, such as pH, enzyme, light, heat, magnetic force, and ultrasound.…”

Deep Tumor Penetration of CRISPR-Cas System for Photothermal-Sensitized Immunotherapy via Probiotics

“…Consisting of numerous antitumor immune cells such as natural killer cells and cytotoxic T lymphocytes , as well as regulatory T cells (Tregs) and myeloid-derived suppressor cells with pro-tumor functions, the tumor immune microenvironment plays a significant role in tumor immune surveillance and immune escape. − However, insufficient T cell infiltration and limited penetration of immune agents in solid tumors remain major obstacles for efficient antitumor immunity, resulting in poor responsive rates among cancer patients . Regulating the tumor infiltration of therapeutic agents could alleviate both proliferation and metastasis of solid tumors, with improved T cell infiltration and subsequent tumor immunity. − Moreover, more aggressive and metastasizing subclones originated preferentially from the center of solid tumors, with a more unstable genome resulting from harsh hypoxic environmental conditions . Thus, eliciting antitumor immune responses in the tumor center with efficient drug penetration into deep tumors is a promising method for tumor therapy.…”