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Multiple machine learning algorithms construct an immunotherapy subgroup model, and in vitro experiments validate HOXC13 regulation of BRCA immunity. 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\nShimonoseki City University, Japan  \nREVIEWED BY  \nXinpei Deng,  \nSun Yat-sen University Cancer Center (SYSUCC), China  \nXiaotong Sun,  \nYantai Yuhuangding Hospital, China  \n*CORRESPONDENCE  \nJingshuai Wang  \n[wangjs90@126.com](wangjs90@126.com)  \n†These authors have contributed equally to this work  \nRECEIVED 03 March 2025  \nACCEPTED 11 July 2025  \nPUBLISHED 08 August 2025  \nCITATION  \nDai 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.  \nFront. Immunol. 16:1586877 .  \ndoi: 10.3389/fimmu.2025.1586877  \nCOPYRIGHT  \n© 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.  \nAn immunotherapy guide constructed by cGAS-STING signature for breast cancer and the biofunction validation of the pivotal gene HOXC13 via in vitro experiments  \nZhenling Dai 1†, Ziqun Gu 2†, Rongrong Shen 1 and Jingshuai Wang 3*  \n1 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  \nObjective: 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.  \nMethods: 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.  \nResults: 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 .  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \nConclusion: 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","cbCaio9HPtUpLyph","https://ap.wps.com/l/cbCaio9HPtUpLyph","pdf",19191906,18,"English","# Objective\n# Methods\n# Results\n# Conclusion\n# Introduction","[{\"question\":\"What is the main objective of the study?\",\"answer\":\"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.\"},{\"question\":\"How were the immunotherapy-related gene signatures constructed?\",\"answer\":\"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.\"},{\"question\":\"What did the in vitro experiments confirm?\",\"answer\":\"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.\"}]","An immunotherapy guide constructed by cGAS-STING signature for breast cancer and the biofunction validation of the pivotal gene HOXC13 via in vitro experiments | PDF",1790165727,45]