{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:05:04Z","timestamp":1784009104705,"version":"3.55.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"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:p>Breast cancer immunity depends on more than the number of immune cells in a tumor. It is also shaped by where those cells sit, which neighbors they contact, and what functional states they adopt locally. Tumor-associated macrophages (TAMs) and T cells are a key pairing in this setting. Depending on tissue context, their crosstalk may support cytotoxic immunity, reinforce immune exclusion, promote T-cell exhaustion, or weaken therapeutic response. Spatial technologies now allow these states to be examined in intact tumor sections rather than inferred from dissociated or bulk samples. Antibody-based imaging approaches, including imaging mass cytometry, MIBI, and CODEX, together with high-plex transcriptomic platforms such as MERFISH, Xenium, CosMx, Visium, GeoMx, and related methods, have revealed inflamed, excluded, myeloid-rich, stromal-barrier, and tertiary lymphoid structure-associated niches in breast cancer. However, spatial maps alone cannot establish mechanism. Cells that lie close together may not necessarily interact, and computational tools, including ligand-receptor scoring, graph-based neighborhood modeling, and spatial biomarker prediction, can only prioritize candidate macrophage-T cell programs. Functional validation remains essential. In this mini review, we discuss how spatial omics, computational modeling, organoid and explant cultures, microfluidic models, perturbation assays, and therapeutic testing can be linked to study macrophage-T cell crosstalk. We highlight a practical workflow in which spatial maps generate hypotheses, experimental systems test causality, and post-treatment profiling determines whether candidate interactions are remodeled by therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1870393","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:37:41Z","timestamp":1784007461000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling macrophage-T cell interactions in the breast cancer immune microenvironment: from spatial omics to functional validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhe","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Breast Surgery, The Affiliated Hospital of Beihua University","place":["Jilin, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, The Second Affiliated Hospital of Army Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Jilin People\u2019s Hospital","place":["Jilin, Jilin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: new dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov"},{"key":"B2","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":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.66","article-title":"Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease","volume":"13","author":"Bianchini","year":"2016","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu450","article-title":"The evaluation of tumor-infiltrating lymphocytes in breast cancer: recommendations by an International TILs Working Group 2014","volume":"26","author":"Salgado","year":"2015","journal-title":"Ann Oncol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-associated macrophages as treatment targets in oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"10215","DOI":"10.1038\/s41467-025-64990-y","article-title":"Systematic benchmarking of imaging spatial transcriptomics platforms in FFPE tissues","volume":"16","author":"Wang","year":"2025","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1016\/j.cell.2018.08.039","article-title":"A structured tumor-immune microenvironment in triple-negative breast cancer revealed by multiplexed ion beam imaging","volume":"174","author":"Keren","year":"2018","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01041-y","article-title":"Breast tumor microenvironment structures are associated with genomic features and clinical outcome","volume":"54","author":"Danenberg","year":"2022","journal-title":"Nat Genet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI96313","article-title":"Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers","volume":"129","author":"Gruosso","year":"2019","journal-title":"J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-020-0026-6","article-title":"Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer","volume":"1","author":"Ali","year":"2020","journal-title":"Nat Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1016\/j.cell.2018.11.021","article-title":"Organoid modeling of the tumor immune microenvironment","volume":"175","author":"Neal","year":"2018","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01398-3","article-title":"An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer","volume":"27","author":"Voabil","year":"2021","journal-title":"Nat Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.ccell.2025.12.009","article-title":"Spatial omics at the forefront: emerging technologies, analytical innovations, and clinical applications","volume":"44","author":"Liu","year":"2026","journal-title":"Cancer Cell"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.868813","article-title":"Mapping breast cancer microenvironment through single-cell omics","volume":"13","author":"Tan","year":"2022","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/S1470-2045(17)30904-X","article-title":"Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy","volume":"19","author":"Denkert","year":"2018","journal-title":"Lancet Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1126\/science.aaf2403","article-title":"Visualization and analysis of gene expression in tissue sections by spatial transcriptomics","volume":"353","author":"St\u00e5hl","year":"2016","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01323-8","article-title":"A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer","volume":"27","author":"Bassez","year":"2021","journal-title":"Nat Med"},{"key":"B18","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":"B19","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020107333","article-title":"A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast","volume":"40","author":"Pal","year":"2021","journal-title":"EMBO J"},{"key":"B20","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.cell.2021.12.023","article-title":"Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma","volume":"185","author":"Risom","year":"2022","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"8499","DOI":"10.1038\/s41467-025-63414-1","article-title":"Comparison of imaging-based single-cell-resolution spatial transcriptomics profiling platforms using formalin-fixed paraffin-embedded tumor samples","volume":"16","author":"Ozirmak Lermi","year":"2025","journal-title":"Nat Commun"},{"key":"B22","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13059-026-03937-y","article-title":"A technical comparison of spatial transcriptomics platforms across six cancer types","volume":"27","author":"Cervilla","year":"2026","journal-title":"Genome Biol"},{"key":"B23","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":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0382-2","article-title":"The adenosine pathway in immuno-oncology","volume":"17","author":"Allard","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41576-020-00292-x","article-title":"Deciphering cell-cell interactions and communication from gene expression","volume":"22","author":"Armingol","year":"2021","journal-title":"Nat Rev Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01358-2","article-title":"Squidpy: a scalable framework for spatial omics analysis","volume":"19","author":"Palla","year":"2022","journal-title":"Nat Methods"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01264-7","article-title":"Deep learning and alignment of spatially resolved single-cell transcriptomes with Tangram","volume":"18","author":"Biancalani","year":"2021","journal-title":"Nat Methods"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01467-z","article-title":"Modeling intercellular communication in tissues using spatial graphs of cells","volume":"41","author":"Fischer","year":"2023","journal-title":"Nat Biotechnol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01469-w","article-title":"LIANA+ provides an all-in-one framework for cell-cell communication inference","volume":"26","author":"Dimitrov","year":"2024","journal-title":"Nat Cell Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06498-3","article-title":"Spatial predictors of immunotherapy response in triple-negative breast cancer","volume":"621","author":"Wang","year":"2023","journal-title":"Nature"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01728-4","article-title":"Screening cell-cell communication in spatial transcriptomics via collective optimal transport","volume":"20","author":"Cang","year":"2023","journal-title":"Nat Methods"},{"key":"B32","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s13059-022-02663-5","article-title":"Explainable multiview framework for dissecting spatial relationships from highly multiplexed data","volume":"23","author":"Tanevski","year":"2022","journal-title":"Genome Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1038\/s41467-022-29439-6","article-title":"Deciphering spatial domains from spatially resolved transcriptomics with an adaptive graph attention auto-encoder","volume":"13","author":"Dong","year":"2022","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1038\/s41467-023-36796-3","article-title":"Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST","volume":"14","author":"Long","year":"2023","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41588-023-01588-4","article-title":"CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity","volume":"56","author":"Varrone","year":"2024","journal-title":"Nat Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005991","article-title":"PhysiCell: an open source physics-based cell simulator for 3-D multicellular systems","volume":"14","author":"Ghaffarizadeh","year":"2018","journal-title":"PloS Comput Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2026.101536","article-title":"mosna reveals different types of cellular interactions predictive of response to immunotherapies and survival in cancer","volume":"25","author":"Coullomb","year":"2026","journal-title":"Mol Cell Proteomics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.cell.2017.11.010","article-title":"A living biobank of breast cancer organoids captures disease heterogeneity","volume":"172","author":"Sachs","year":"2018","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1158\/2159-8290.CD-17-0833","article-title":"Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids","volume":"8","author":"Jenkins","year":"2018","journal-title":"Cancer Discov"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-00474-1","article-title":"Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids","volume":"16","author":"Dekkers","year":"2021","journal-title":"Nat Protoc"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-006290","article-title":"Emerging organoid-immune co-culture models for cancer research: from oncoimmunology to personalized immunotherapies","volume":"11","author":"Magr\u00e9","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202303658","article-title":"Engineered tumor-immune microenvironment on a chip to study T cell-macrophage interaction in breast cancer progression","volume":"13","author":"Manoharan","year":"2024","journal-title":"Adv Healthc Mater"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2018.08.010","article-title":"Tumor-associated macrophages in breast cancer: innocent bystander or important player","volume":"70","author":"Qiu","year":"2018","journal-title":"Cancer Treat Rev"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.02.003","article-title":"Targeting tumor-associated macrophages in cancer","volume":"40","author":"Pathria","year":"2019","journal-title":"Trends Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nature19834","article-title":"PI3K\u03b3 is a molecular switch that controls immune suppression","volume":"539","author":"Kaneda","year":"2016","journal-title":"Nature"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.04.084","article-title":"Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis","volume":"15","author":"Georgoudaki","year":"2016","journal-title":"Cell Rep"},{"key":"B47","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41392-021-00484-9","article-title":"Targeting tumor-associated macrophages to synergize tumor immunotherapy","volume":"6","author":"Xiang","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1016\/j.cell.2022.02.015","article-title":"Spatial CRISPR genomics identifies regulators of the tumor microenvironment","volume":"185","author":"Dhainaut","year":"2022","journal-title":"Cell"},{"key":"B49","doi-asserted-by":"publisher","first-page":"2141","DOI":"10.1016\/j.cell.2025.02.012","article-title":"Simultaneous CRISPR screening and spatial transcriptomics reveal intracellular, intercellular, and functional transcriptional circuits","volume":"188","author":"Binan","year":"2025","journal-title":"Cell"},{"key":"B50","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":"B51","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2202809","article-title":"Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer","volume":"387","author":"Cortes","year":"2022","journal-title":"N Engl J Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era of cancer immunotherapy","volume":"19","author":"Saut\u00e8s-Fridman","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1914-8","article-title":"Tertiary lymphoid structures improve immunotherapy and survival in melanoma","volume":"577","author":"Cabrita","year":"2020","journal-title":"Nature"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1922-8","article-title":"B cells and tertiary lymphoid structures promote immunotherapy response","volume":"577","author":"Helmink","year":"2020","journal-title":"Nature"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1906-8","article-title":"B cells are associated with survival and immunotherapy response in sarcoma","volume":"577","author":"Petitprez","year":"2020","journal-title":"Nature"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1870393\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:37:42Z","timestamp":1784007462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1870393\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2026.1870393"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1870393","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]},"article-number":"1870393"}}