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Deciphering the CAF‑LCN2 axis: Key to overcoming anti‑PD‑L1 immunotherapy resistance in lung cancer

Dan Xiao1, Jing Yang2, Jianying Zhou1

  • 1Department of Thoracic Oncology, Jiangxi Clinical Research Center for Cancer, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Key Laboratory of Oncology, Jiangxi Cancer Hospital and Institute, Nanchang, Jiangxi 330029, P.R. China.

International Journal of Molecular Medicine
|January 23, 2026
PubMed

Insights

Cancer-associated fibroblasts promote lung cancer immunotherapy resistance via lipocalin 2. Targeting this CAF-LCN2 axis can enhance anti-PD-1 therapy efficacy by inducing ferroptosis and suppressing tumor growth.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Lung cancer has a high mortality rate, and resistance to immunotherapy, such as anti-programmed cell death protein 1 (PD-1) therapy, is a significant clinical challenge.
  • Understanding the molecular mechanisms of therapeutic resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the molecular characteristics of lung cancer and identify mechanisms of resistance to anti-PD-1 immunotherapy.
  • To elucidate the role of cancer-associated fibroblasts (CAFs) and lipocalin 2 (LCN2) in mediating immunotherapy resistance.

Main Methods:

  • Single-cell RNA sequencing was employed to analyze lung cancer molecular profiles.
  • Functional assays (CCK-8, EdU, TUNEL, Transwell) and molecular/histological analyses were performed.
  • LCN2 expression and its impact on tumor growth, invasion, immune infiltration, and ferroptosis were assessed.

Main Results:

  • Cancer-associated fibroblasts (CAFs) were identified as key players in promoting immune resistance.
  • CAFs regulate lipocalin 2 (LCN2) expression in lung cancer cells; elevated LCN2 enhances proliferation, invasion, and immunotherapy resistance.
  • Silencing LCN2 induced ferroptosis in lung cancer cells, increasing sensitivity to anti-PD-1 therapy, suppressing tumor growth, and reducing invasiveness.

Conclusions:

  • The cancer-associated fibroblast (CAF)-lipocalin 2 (LCN2) axis is critical in mediating resistance to anti-PD-1 immunotherapy in lung cancer.
  • Targeting the CAF-LCN2 pathway, potentially by inducing ferroptosis, offers a promising strategy to overcome therapeutic resistance and improve anti-PD-1 treatment efficacy.
Keywords:
fibroblastimmunotherapylipocalin‑2lung cancerresistancesingle‑cell transcript­omics

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