Activated T-cell membrane-derived nanocargoes displaying multi-immune checkpoints for enhanced cancer immunotherapy

TL;DR

Researchers developed nanocarriers from activated T-cell membranes to block multiple immune checkpoints and improve cancer immunotherapy effectiveness.

Contribution

A novel nanocarrier system using activated T-cell membranes to simultaneously block multiple immune checkpoints and enhance T-cell infiltration.

Findings

AM-dLNPs effectively inhibit multiple immune checkpoint pathways through competitive blockade and ligand down-regulation.

AM-dLNPs promote intratumoral T cell infiltration and reduce tumor progression in mouse models.

AM-dLNPs show exceptional biosafety and tumor-targeting properties for potential clinical use.

Abstract

The advent of immune checkpoint inhibitors (ICIs) has significantly transformed the landscape of cancer treatment in the last decade. However, the efficacy of single-agent ICI remains constrained due to multiple immune checkpoints (ICs)-mediated T cell suppression and inadequate T cell tumor infiltration. Here, we developed a novel approach using activated T-cell membrane-guided nanocarriers to simultaneously block multiple ICs and enhance T-cell infiltration. Initially, primary T cell activation was induced in vitro, and T cells with high expression of ICs were selected to prepare T-cell membrane vesicles. These vesicles were then utilized to coat immunogenic inducer-loaded liposomes (dLNPs) to create nanocarriers termed AM-dLNPs. The AM-dLNPs were demonstrated to effectively inhibit multiple ICs pathways through competitive blockade of immune checkpoint ligand-receptor interactions and down-regulation of immune checkpoint ligand expression. Additionally, the AM-dLNPs exhibited a strong ability to promote intratumoral T cell infiltration through targeted delivery of the immunogenic inducer. Benefiting from the exceptional biosafety profile, multi-ICs blockade efficacy, and tumor-targeting properties of the T-cell membrane vesicles, administration of AM-dLNPs resulted in a significant reduction in tumor progression and notable survival advantages in various mouse tumor models. These findings provide a basis for the clinical assessment of activated T-cell membrane-derived nanocarriers, which solves the dilemma of limited effects of ICI treatment without biosafety concerns. Its versatility also enables the targeted delivery of other immunogenic agents for synergistic antitumor immunotherapies.

Image 1

•STING agonist-mediated anti-tumor effects require synergistic multi-checkpoint blockade.•Activated T-cell membrane vesicles possess multi-checkpoint blocking ability.•Activated T-cell membrane-coated nanocargoes precisely deliver STING agonist to enhance tumor immunogenicity.•Activated T-cell membrane-coated nanocargoes boost immunogenicity and block checkpoints for potent anti-tumor efficacy.

STING agonist-mediated anti-tumor effects require synergistic multi-checkpoint blockade.

Activated T-cell membrane vesicles possess multi-checkpoint blocking ability.

Activated T-cell membrane-coated nanocargoes precisely deliver STING agonist to enhance tumor immunogenicity.

Activated T-cell membrane-coated nanocargoes boost immunogenicity and block checkpoints for potent anti-tumor efficacy.

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