The G-quadruplex ligand CX-5461 inhibits laryngeal cancer via inducing immunogenic cell death and remodeling the tumor immune microenvironment.

Authors

Fang-Yuan Teng, Bo Zhang, Yue-Xi Liu, Qi Wu, Yong Xu, Gang Qin, Hong-Xia Li

Published in

International immunopharmacology. Volume 187. Pages 117229. Aug 10, 2026. Epub Aug 10, 2026.

Abstract

G-quadruplex (G4) structures, formed by guanine-rich nucleic acids, are implicated in tumor progression and represent promising therapeutic targets. In laryngeal cancer, the profile and clinical relevance of G4s, as well as the efficacy of G4 ligands, remain unexplored. This study aims to examine the clinical significance of G4 accumulation and investigate the antitumor and immunomodulatory mechanisms of the G4 ligand in laryngeal cancer.
G4 formation was analyzed in laryngeal cancer and adjacent normal tissues by immunohistochemistry (IHC), and its correlation with patient prognosis was evaluated by Kaplan-Meier survival curves. In vitro, the effects of G4 ligand CX-5461 and Pyridostatin (PDS) on cell proliferation, apoptosis, and cell cycle were assessed. Tumor cells were co-cultured with dendritic cells (DC), and the immunogenic cell death (ICD) of tumor cells was detected by ELISA and immunofluorescence. The DC maturation was also examined by flow cytometry analysis and ELISA. In vivo, the antitumor efficacy of G4 ligand alone and in combination with anti-PD-1 was validated in immunocompetent mouse xenograft models. The tumor immune microenvironment was analyzed by flow cytometry.
Clinical data revealed significantly higher G4 levels in laryngeal tumor tissues compared to adjacent normal tissues, with elevated G4 levels closely associated with poor prognosis. In vitro, CX-5461 and PDS induced apoptosis and G2/M cell cycle arrest. CX-5461 significantly inhibited tumor growth in the subcutaneous tumor model of mice, but PDS was poor in vivo. Furthermore, CX-5461 can promote DNA double-strand breaks in SNU1076 and SNU899 cells, increase the expression level of γ-H2AX, and cause the cells' calreticulin (CRT) to protrude outward while increasing the secretion of high mobility group box 1 (HMGB1). When tumor cells treated with CX-5461 are co-cultured with DC cells, it can promote the increase in the expression of CD80 and CD86 on DC cells, and also increase the secretion of cytokines IL-6, IL-12, and TNF-α. In vivo, CX-5461 significantly suppressed tumor growth and enhanced infiltration of CD8⁺ T cells, CD45⁺ immune cells, and DCs in the tumor microenvironment. Combined therapy with CX-5461 and anti-PD-1 demonstrated a striking synergistic antitumor effect in vivo.
G4 is a novel prognostic biomarker for laryngeal cancer. CX-5461 exerts anti-laryngocarcinoma effects by inducing ICD and reshaping the tumor immune microenvironment, providing a strong preclinical rationale for combining CX-5461 with immune checkpoint blockade in laryngeal cancer treatment.

PMID:
42574810
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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