2. Academic Validation
  3. ITGA5-expressing tumor cells interact with Schwann cells to drive nerve growth factor-mediated immunosuppression of NK cells

ITGA5-expressing tumor cells interact with Schwann cells to drive nerve growth factor-mediated immunosuppression of NK cells

  • Mol Ther. 2025 Jul 28:S1525-0016(25)00579-9. doi: 10.1016/j.ymthe.2025.07.043.
Yingqiao Liu 1,  Guoxu Han 2,  Kang Feng 1,  Xiaoyang Lin 1,  Weijun Zhong 1,  Yilian Liu 1,  Cheng Wang 3,  Caihua Zhang 4,  Xiqiang Liu 5
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 2 Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, and Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China.
  • 3 Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510030, China.
  • 4 Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 5 Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: liuxiqiang@smu.edu.cn.
PMID: 40734271 DOI: 10.1016/j.ymthe.2025.07.043
Abstract

Perineural invasion (PNI) complicates Cancer treatment by promoting tumor spread and immune evasion through interactions between tumor cells and peripheral nerves in the tumor microenvironment (TME). This study investigates the role of tumor cells in PNI and their impact on neuro-immunomodulation. We identified a strong correlation between elevated ITGA5 expression and PNI, both associated with poor clinical outcomes due to their contribution to an immunosuppressive TME. Specifically, high ITGA5 expression in tumor cells increased nerve density and reduced natural killer cell infiltration, facilitating immune evasion. Functional assays revealed that the interaction between ITGA5 on tumor cells and fibronectin (FN1) in the SC extracellular matrix triggers the reprogramming of SCs to a reparative phenotype, enhancing nerve growth factor (NGF) secretion and promoting tumor neurogenesis. Increased NGF suppresses NK cell cytotoxicity by inhibiting interferon-γ, further supporting tumor growth. Additionally, cilengitide significantly improves anti-programmed cell death protein-1 immunotherapy efficacy, offering a potential therapeutic strategy to counteract PNI-driven immunosuppression. This study identifies ITGA5 as a key promoter of tumor invasion into nerves, enhancing NGF release from Schwann cells and altering the immune landscape to favor tumor growth. These findings open new avenues for therapies targeting these interactions in Cancer progression.

Keywords

ITGA5; Schwann cell; natural killer cell; nerve growth factor; perineural invasion.

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