An immunotherapy guide constructed by cGAS-STING signature for breast cancer and the biofunction validation of the pivotal gene HOXC13 via in vitro experiments

Sep 23, 2026

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Immunotherapy has become a pivotal element in breast cancer treatment, especially for cases resistant to traditional approaches. This study investigates how the cGAS-STING pathway contributes to immunotherapy resistance and aims to define predictive biomarkers. Multiple machine learning algorithms construct an immunotherapy subgroup model, and in vitro experiments validate HOXC13 regulation of BRCA immunity. A 11-gene signature distinguishes high- and low-response groups across independent GEO cohorts and supports prediction of response to conventional and immune therapies.

LanguageEnglish

CategoryHealthcare

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Pages18

Reading Time45 min

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Objective

Methods

Results

Conclusion

Introduction

TYPE Original Research PUBLISHED 08 August 2025 DOI 10.3389/fimmu.2025.1586877 OPEN ACCESS EDITED BY Ming Xu, Shimonoseki City University, Japan REVIEWED BY Xinpei Deng, Sun Yat-sen University Cancer Center (SYSUCC), China Xiaotong Sun, Yantai Yuhuangding Hospital, China *CORRESPONDENCE Jingshuai Wang [wangjs90@126.com](wangjs90@126.com) †These authors have contributed equally to this work RECEIVED 03 March 2025 ACCEPTED 11 July 2025 PUBLISHED 08 August 2025 CITATION Dai Z, Gu Z, Shen R and Wang J (2025) An immunotherapy guide constructed by cGASSTING signature for breast cancer and the biofunction validation of the pivotal gene HOXC13 via in vitro experiments. Front. Immunol. 16:1586877 . doi: 10.3389/fimmu.2025.1586877 COPYRIGHT © 2025 Dai, Gu, Shen and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. An immunotherapy guide constructed by cGAS-STING signature for breast cancer and the biofunction validation of the pivotal gene HOXC13 via in vitro experiments Zhenling Dai 1†, Ziqun Gu 2†, Rongrong Shen 1 and Jingshuai Wang 3* 1 Department of General Surgery, Shanghai Sixth People’s Hospital, Shanghai, China, 2 Department of Breast Surgery, International Peace Maternal and Child Health Hospital of China Welfare Society, Shanghai, China, 3 Department of Obstetrics and Gynecology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China Objective: As the most common cancer in women, immunotherapy has become a pivotal element in the treatment of breast cancer, particularly for cases resistant to traditional therapies. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is recognized as the primary DNA-sensing mechanism that initiates immune and inﬂammatory responses. In this study, we aim to explore the role of the cGAS-STING pathway in breast cancer immunotherapy resistance. Methods: Multiple machine learning algorithms were applied to construct an immunotherapy subgroup model and in vitro experiments were performed to verify the HOXC13 in regulating BRCA immunity. Results: Building upon extensively researched genes within the cGAS-STING pathway, we identiﬁed eight genes that serve as indicators of breast cancer’s responsiveness to anti-PD1 therapy. Through consensus clustering, patients were categorized into high-response and low-response groups based on these eight genes. Subsequently, we extracted the pivotal gene set by WGCNA, which showed the highest correlation with the response to immune therapy, followed by the selection of 11 genes, which held signiﬁcant associations with Tcell exhaustion, immune score, and patient survival. Employing machine learning, our novel classiﬁcation model based on the 11-gene signature effectively differentiated between high-response and low-response groups in 16 out of 18 independent breast cancer cohorts from the GEO database. Notably, this 11-gene signature also predicted the sensitivity of breast cancer to both conventional and immune therapies, aligning closely with predictions from the OncoPredict algorithm. Further, in-vitro experiments conﬁrmed the regulatory role of HOXC13, one of the 11 genes, in the cGAS-STING pathway. Moreover, miR-26a-5p, a microRNA previously identiﬁed as a suppressor in breast cancer, was demonstrated to regulate HOXC13 . Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) Conclusion: Our study implies that HOXC13 is a potential therapy target for BRCA immunotherapy and 11-gene signature is a potential tool for clinical evaluation of anti-PD1

FAQs

What is the main objective of the study?

To explore the role of the cGAS-STING pathway in breast cancer immunotherapy resistance and to identify biomarkers that predict response to anti-PD1 therapy.

How were the immunotherapy-related gene signatures constructed?

Multiple machine learning algorithms were used to build an immunotherapy subgroup model, and gene selection was refined using consensus clustering and WGCNA, followed by additional selection linked to T-cell exhaustion, immune score, and survival.

What did the in vitro experiments confirm?

The experiments confirmed that HOXC13, one of the 11 genes in the signature, regulates the cGAS-STING pathway, and miR-26a-5p regulates HOXC13 in breast cancer.

Sep 23, 2026

Uploaded by Grenda