Locked Dimerized CXCL12 Exerts Radiosensitizing Effects in Head and Neck Cancer

Document Type

Article

Publication Date

5-2025

Publisher

Wiley

Source Publication

Head & Neck

Source ISSN

1043-3074

Original Item ID

DOI: 10.1002/hed.28048

Abstract

Background

Head and neck squamous cell carcinoma (HNSCC) presents significant treatment challenges, particularly in cases unrelated to human papillomavirus (HPV). The chemokine receptor CXCR4, interacting with its ligand CXCL12, plays a crucial role in tumor proliferation, metastasis, and treatment resistance. This study explores the therapeutic potential of engineered monomeric and dimerized CXCL12 variants (CXCL121 and CXCL122, respectively) in HNSCC and evaluates potential additive effects when combined with radiation therapy.

Methods

Clinical HNSCC biopsies were evaluated for CXCR4 expression in both previously untreated and radiorecurrent disease. HNSCC cell lines were then treated with combinations of CXCL12 variants and radiotherapy and interrogated for proliferation, gene expression change, and underlying molecular mechanisms. In vivo studies evaluated the biodistribution of engineered CXCL12 and tested these treatments in humanized cell line-derived xenograft (CDX) models.

Results

CXCL122 significantly reduced HNSCC cell proliferation and enhanced the effects of radiotherapy, likely through biased agonism at the CXCR4 receptor and upregulation of the KISS1R pathway. In vivo, CXCL122 localized to tumor sites and augmented the effects of radiation to inhibit tumor growth.

Conclusions

CXCL122, in combination with radiation, demonstrates potent anti-tumor effects in HNSCC. These findings support further clinical investigation of CXCL122 to enhance the effects of radiotherapy.

Comments

Head & Neck, Vol. 47, No. 5 (May 2025): 1379-1391. DOI.

Link to Full Text

Share

COinS