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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background: The cyclic GMP-AMP synthase (cGAS)–type I interferon (IFN-I) pathway detects cytoplasmic DNA and triggers immune responses. Cancer cells often suppress this pathway to evade immune surveillance; however, its therapeutic potential remains unclear. Methods: Mouse oral squamous cell carcinoma models, representing a prominent subtype of head and neck squamous cell carcinoma (HNSCC), were employed in this study. Flow cytometry, Western blot, ELISA, and PCR were used for analysis. Results: We found that immune-unresponsive MOC2 tumors exhibited a deficiency of antigen-presenting cells and cytotoxic T lymphocytes, along with a significant suppression of the cGAS-IFN-I pathway, compared to immune-responsive MOC1 tumors. An MOC2-conditioned medium impaired the differentiation of bone marrow-derived cells into dendritic cells (DCs), reducing the expression of DC markers as well as class I and II major histocompatibility complex (MHC) molecules. The activation of the cGAS-IFN-I pathway in MOC2 cells, either through exogenous DNA or direct IFN-I expression, enhanced class I MHC expression and antigen presentation on MOC2 cells. Furthermore, IFNB1 expression in MOC2 cells induced apoptosis and upregulated chemokines, such as CXCL9 and CXCL10, which recruit immune cells. In immunocompetent mice, IFNB1 expression suppressed MOC2 tumor growth by attracting DCs and T cells, an effect amplified by co-expressing the granulocyte–macrophage colony-stimulating factor. Conclusions: These findings highlight the potential of enhancing cancer cell-intrinsic cGAS-IFN-I signaling to improve tumor immune surveillance and control the progression of immune-cold HNSCC tumors.

Details

Title
Cancer Cell-Intrinsic Type I Interferon Signaling Promotes Antitumor Immunity in Head and Neck Squamous Cell Carcinoma
Author
Xie Guiqin 1   VIAFID ORCID Logo  ; Yang Cuicui 1 ; Pang Xiaowu 2 ; Wu Tzyy-Choou 3 ; Gu Xinbin 1   VIAFID ORCID Logo 

 Department of Oral Pathology, Howard University, 600 W Street NW, Washington, DC 20059, USA; [email protected] (C.Y.); [email protected] (X.P.), Cancer Center, Howard University, 2041 Georgia Avenue NW, Washington, DC 20059, USA 
 Department of Oral Pathology, Howard University, 600 W Street NW, Washington, DC 20059, USA; [email protected] (C.Y.); [email protected] (X.P.) 
 Pathology, Oncology, Obstetrics & Gynecology, and Molecular Microbiology & Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; [email protected] 
First page
1279
Publication year
2025
Publication date
2025
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3194505121
Copyright
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.