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

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

  • J Pharm Anal. 2025 Dec;15(12):101309. doi: 10.1016/j.jpha.2025.101309.
Na Liu 1 2 3 4,  Yuzhen Tu 5,  Hanyu Wang 6,  Xiaoqiang Zheng 3 4,  Fanpu Ji 1,  Mingsha Geng 7,  Xin Wei 4 8,  Jingman Xin 9,  Wangxiao He 4,  Qian Zhao 10 11,  Tianya Liu 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Infectious Diseases and Hepatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
  • 2 Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, Hainan Medical University, Haikou, 571199, China.
  • 3 Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
  • 4 Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 5 Department of Clinical Laboratory, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361000, China.
  • 6 Faculty of Arts and Science, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
  • 7 Department of Network Information, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
  • 8 Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.
  • 9 School of Stomatology, Xi'an Jiaotong University, Xi'an, 710049, China.
  • 10 Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
  • 11 Department of Day Surgery Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
PMID: 41492455 DOI: 10.1016/j.jpha.2025.101309
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.

Keywords

Cancer therapy; Immunotherapy; Non-small cell lung cancer; Tumor microenvironment; Wnt/β-catenin signal.

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