{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T06:11:45Z","timestamp":1777961505269,"version":"3.51.4"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Precision medicine emphasizes accurate patient stratification. However, existing molecular frameworks often fail to fully capture the intrinsic heterogeneity of breast cancer (BRCA). This study aims to establish a novel immune-based classification system using immunological gene sets to elucidate tumor heterogeneity and identify predictive biomarkers for optimizing clinical management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Non-negative Matrix Factorization (NMF) analysis of Gene Set Variation Analysis enrichment scores, transformed from TCGA, GEO, and CCLE transcriptomic profiles, revealed distinct immune subtypes. These subtypes were comprehensively characterized for their immune, mutational, and molecular features. Therapeutic sensitivity was assessed using computational prediction algorithms and validated via\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments. Finally, subtype-specific hub genes were identified through co-expression network analysis (WGCNA) and experimentally confirmed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Three distinct immune subtypes were identified. Cluster II exhibited a survival advantage, high immune infiltration, and strong correlation with Basal-like tumors. In contrast, Cluster I aligned with Luminal subtypes and indicated poor prognosis. Therapeutic analysis revealed that Cluster II is most likely to benefit from immunotherapy. Additionally, five identified hub genes further confirmed the stability and accuracy of this immune stratification system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrated that classifying identification of immune patterns for individual tumor patients could reveal the complexity of tumor immune microenvironment and further optimize precision immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1795917","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T05:32:06Z","timestamp":1777959126000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated characterization of distinct immune subtypes linked to drug responsiveness in breast cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Min","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]},{"name":"Department of Pharmacology, School of Pharmacy, China Medical University","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meina","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, China Medical University","place":["Shenyang, China"]},{"name":"Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo-shi","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, China Medical University","place":["Shenyang, China"]},{"name":"Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.21147\/j.issn.1000-9604.2025.02.12","article-title":"Different strategies for cancer treatment: Targeting cancer cells or their neighbors","volume":"37","author":"Liu","year":"2025","journal-title":"Chin J Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32381-3","article-title":"Breast cancer","volume":"397","author":"Loibl","year":"2021","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.cancergen.2025.03.004","article-title":"Identification of new immune target and signaling for cancer immunotherapy","author":"Narote","year":"2025","journal-title":"Cancer Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/s41573-018-0007-y","article-title":"Approaches to treat immune hot, altered and cold tumours with combination immunotherapies","volume":"18","author":"Galon","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"B9","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1158\/2159-8290.CD-22-0475","article-title":"The great immune escape: Understanding the divergent immune response in breast cancer subtypes","volume":"13","author":"Onkar","year":"2023","journal-title":"Cancer Discov"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv192","article-title":"PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes","volume":"26","author":"Ali","year":"2015","journal-title":"Ann Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00911-1","article-title":"A single-cell and spatially resolved atlas of human breast cancers","volume":"53","author":"Wu","year":"2021","journal-title":"Nat Genet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00387","article-title":"NCAPG is a promising therapeutic target across different tumor types","volume":"11","author":"Xiao","year":"2020","journal-title":"Front Pharmacol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx378","article-title":"CancerSubtypes: an R\/Bioconductor package for molecular cancer subtype identification, validation and visualization","volume":"33","author":"Xu","year":"2017","journal-title":"Bioinformatics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: efficient and comprehensive analysis of somatic variants in cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.168","article-title":"PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas","volume":"14","author":"Goodman","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107468","article-title":"pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels","volume":"9","author":"Geeleher","year":"2014","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3984","article-title":"Pan-cancer analysis of the extent and consequences of intratumor heterogeneity","volume":"22","author":"Andor","year":"2016","journal-title":"Nat Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2022.109244","article-title":"Benefits of combination therapy with immune checkpoint inhibitors and predictive role of tumour mutation burden in hepatocellular carcinoma: A systematic review and meta-analysis","volume":"112","author":"Zheng","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.3390\/cancers13174287","article-title":"Breast cancer-epidemiology, risk factors, classification, prognostic markers, and current treatment strategies-an updated review","volume":"13","author":"\u0141ukasiewicz","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1586\/era.12.147","article-title":"Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade","volume":"12","author":"Emens","year":"2012","journal-title":"Expert Rev Anticancer Ther"},{"key":"B26","article-title":"Immune targeting in breast cancer","volume":"29","author":"Cimino-Mathews","year":"2015","journal-title":"Oncol (Williston Park NY)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2703","article-title":"Innate and adaptive immune cells in the tumor microenvironment","volume":"14","author":"Gajewski","year":"2013","journal-title":"Nat Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.583084","article-title":"Tumor-associated macrophages in tumor immunity","volume":"11","author":"Pan","year":"2020","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1038\/nrd.2018.169","article-title":"Targeting macrophages: therapeutic approaches in cancer","volume":"17","author":"Cassetta","year":"2018","journal-title":"Nat Rev Drug Discov"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0127-6","article-title":"Macrophages as regulators of tumour immunity and immunotherapy","volume":"19","author":"DeNardo","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-019-0760-3","article-title":"Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications","volume":"12","author":"Lin","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0000000000000517","article-title":"Comprehensive molecular analyses of an M2-like tumor-associated macrophage for predicting the prognosis and immunotherapy in breast cancer","volume":"47","author":"Chang","year":"2024","journal-title":"J Immunother"},{"key":"B34","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1006\/mcbr.1999.0155","article-title":"The role of the E-cadherin\/catenin adhesion complex in the development and progression of cancer","volume":"2","author":"Nollet","year":"1999","journal-title":"Mol Cell Biol Res Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1080\/1354750X.2025.2591717","article-title":"Emerging biomarkers in breast cancer: translational and multi-omics perspectives in precision oncology","volume":"30","author":"Yasmin","year":"2025","journal-title":"Biomarkers"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The immune landscape of cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.04.014","article-title":"Conserved pan-cancer microenvironment subtypes predict response to immunotherapy","volume":"39","author":"Bagaev","year":"2021","journal-title":"Cancer Cell"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1809615","article-title":"Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer","volume":"379","author":"Schmid","year":"2018","journal-title":"N Engl J Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028485","article-title":"Sacituzumab govitecan in metastatic triple-negative breast cancer","volume":"384","author":"Bardia","year":"2021","journal-title":"N Engl J Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nri2580","article-title":"New insights into the regulation of T cells by gamma(c) family cytokines","volume":"9","author":"Rochman","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20202898","article-title":"Comprehensive analysis reveals a prognostic and therapeutic biomarker CD3D in the breast carcinoma microenvironment","volume":"41","author":"Zhu","year":"2021","journal-title":"Biosci Rep"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.02.055","article-title":"The next horizon in precision oncology: Proteogenomics to inform cancer diagnosis and treatment","volume":"184","author":"Rodriguez","year":"2021","journal-title":"Cell"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1795917\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T05:32:07Z","timestamp":1777959127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1795917\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,5]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2026.1795917"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1795917","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,5]]},"article-number":"1795917"}}