Reactivating T cell immunity in Wnt-hyperactivated non-small cell lung cancer through a supramolecular droplet of carnosic acid and peptide

Available online 14 April 2025, 101309

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Targeting the activated Wnt/β-catenin signaling pathway in NSCLC effectively achieved antitumor effects and restored T lymphocyte infiltration in TME.

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Design a Supramolecular Droplet of Carnosic Acid and Peptide.

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Pep1@CA significantly restored intratumoural CD8+ T cell infiltration and reduced Treg cell infiltration in the subcutaneous tumor-carrying mouse model.

Abstract

The Wnt/β-catenin signaling pathway is renowned for its contribution to the immunosuppressive microenvironment in non-small cell lung cancer (NSCLC). Consequently, inhibiting this pathway has emerged as a promising strategy to enhance immune activation and reinstate T cell responses in cancer treatment. In this study, we initially investigate the metabolic characteristics of Wnt-hyperactivated NSCLC using mass spectroscopic detection in a mouse in-situ model and unveil its significant feature of acid accumulation at tumor sites. Building upon this discovery, we design an acid-sensitive peptide-carnosic acid (CA) supramolecular droplet, Pep1@CA, which leverages the acidic microenvironment characteristic of NSCLC for controlled release. By doing so, we aim to enhance targeting efficiency while minimizing off-target effects. As anticipated, Pep1@CA demonstrates potent tumor-specific inhibition of the Wnt signaling pathway and effectively reactivates T cell immunity in Wnt-hyperactivated NSCLC. Importantly, comprehensive in vivo evaluations reveal significant antitumor efficacy alongside excellent biosafety profiles. Collectively, this study provides a therapeutic strategy with promising clinical translational potential for targeting the Wnt signaling pathway and offers theoretical support for its application in immunotherapy. This innovative approach underscores that targeting pathways beyond traditional immunotherapy can also activate tumor immunity, thereby expanding the potential of cancer immunotherapy.

Graphical abstractThis study developed a peptide-carnosic acid supramolecular based on the Wnt inhibitor. The supramolecular self-assembly peptide responds to the acidic microenvironment of tumors and specifically targets the Wnt signaling pathway in tumor cells, downregulates Treg cells and restore CD8+ T cell infiltration in the TME, and demonstrates potent antitumor effects.