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TIPE2 regulates LRRC33-Mediated TGF-β1 activation in MDSCs to restrict lung cancer PD-1 blockade immunotherapy

Abdulrahman Ibrahim1, Zihao Liang2, Rong Li2

  • 1Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; University of Chinese Academy of Sciences, Beijing, 100864, China.

Biochemical and Biophysical Research Communications
|September 24, 2025
PubMed

Insights

Targeting the STAT3-TIPE2-LRRC33 pathway in myeloid-derived suppressor cells can overcome resistance to anti-PD-1 therapy in lung cancer by reducing immunosuppressive TGF-β1. This approach enhances antitumor immunity and improves treatment outcomes.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Medicine

Background:

  • Lung cancer immunotherapy with immune checkpoint inhibitors (ICIs) faces resistance, partly due to immunosuppressive myeloid-derived suppressor cells (MDSCs).
  • MDSCs promote an immunosuppressive tumor microenvironment (TME) via transforming growth factor-β1 (TGF-β1) activation, presented on their surface by leucine-rich repeat-containing protein 33 (LRRC33).
  • Intracellular mechanisms regulating LRRC33-mediated TGF-β1 presentation remain unclear.

Purpose of the Study:

  • To investigate the role of tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) in regulating LRRC33-mediated TGF-β1 activation in MDSCs.
  • To explore the STAT3-TIPE2 axis in controlling TIPE2 expression within MDSCs.
  • To evaluate the therapeutic potential of targeting the STAT3-TIPE2-LRRC33 axis in combination with anti-PD-1 therapy for lung cancer.

Main Methods:

  • In vitro MDSC cultures and an in vivo Lewis lung carcinoma (LLC) mouse model.
  • Western blot, ELISA, flow cytometry, chromatin immunoprecipitation, and luciferase reporter assays.
  • Pharmacological inhibition of STAT3.

Main Results:

  • TIPE2 deficiency significantly reduced LRRC33 expression and surface TGF-β1 localization in MDSCs, suppressing tumor growth.
  • STAT3 was identified as a transcriptional regulator of TIPE2 in MDSCs.
  • Pharmacological inhibition of STAT3 mimicked TIPE2 loss, reducing TGF-β1 and synergizing with anti-PD-1 therapy.

Conclusions:

  • The STAT3-TIPE2-LRRC33 axis acts as a novel intracellular checkpoint controlling localized TGF-β1 activation in MDSCs.
  • Targeting this axis offers a promising strategy to enhance antitumor immunity and overcome resistance to PD-1 blockade in lung cancer.
  • This pathway represents a potential therapeutic target for improving lung cancer treatment outcomes.
Keywords:
Immune checkpoint blockadeLung cancerMDSCsSTAT3TGF-β1TIPE2

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