{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T03:31:30Z","timestamp":1777606290010,"version":"3.51.4"},"reference-count":59,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T00:00:00Z","timestamp":1670630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The tumor microenvironment (TME) is a complex and constantly changing entity. The TME consists of stromal cells, fibroblasts, endothelial cells, and innate and adaptive immune cells. Cancer development and progression occurs through this interplay between the tumor and the adjacent stroma. Cancer cells are capable of modifying their microenvironment by secreting various message-carrying molecules, such as cytokines, chemokines, and other factors. This action causes a reprogramming of the neighboring cells, which are enabled to play a crucial role in tumor survival and progression. The study of TME has many clinical implications in terms of cancer therapeutics because many new drugs, such as antibodies, kinase inhibitors, and liposome formulations that can encapsulate anti-cancer drugs, can be developed. Although chemotherapy is considered the standard of treatment for advanced disease, recent research has brought to light immunotherapy as a possible systemic alternative. However, the complex structure and function of the thymus hinders its routine use in clinical practice. The aim of this review paper is to discuss the recent advances in the investigation of the unique characteristics of the TME of thymic epithelial tumors that could possibly lead to the development of novel promising therapies.<\/jats:p>","DOI":"10.3390\/cancers14246082","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T04:05:22Z","timestamp":1670817922000},"page":"6082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Tumor Microenvironment in Thymic Epithelial Tumors: A Narrative Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7525-2080","authenticated-orcid":false,"given":"Apostolos C.","family":"Agrafiotis","sequence":"first","affiliation":[{"name":"Department of Thoracic and Vascular Surgery, Antwerp University Hospital, University of Antwerp, B-2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8608-4660","authenticated-orcid":false,"given":"Vasiliki","family":"Siozopoulou","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Antwerp University Hospital, University of Antwerp, B-2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9145-3643","authenticated-orcid":false,"given":"Jeroen M. H.","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Vascular Surgery, Antwerp University Hospital, University of Antwerp, B-2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Pauwels","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Antwerp University Hospital, University of Antwerp, B-2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Senada","family":"Koljenovic","sequence":"additional","affiliation":[{"name":"Laboratory of Pathology, Antwerp University Hospital, University of Antwerp, B-2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1962-8821","authenticated-orcid":false,"given":"Paul E.","family":"Van Schil","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Vascular Surgery, Antwerp University Hospital, University of Antwerp, B-2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.copbio.2016.02.007","article-title":"Impact of the physical microenvironment on tumor progression and metastasis","volume":"40","author":"Spill","year":"2016","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1158\/0008-5472.CAN-18-3962","article-title":"The tumor microenvironment innately modulates cancer progression","volume":"79","author":"Hinshaw","year":"2019","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"408","DOI":"10.3390\/cancers3010408","article-title":"Tumor Acidity as Evolutionary Spite","volume":"3","author":"Alfarouk","year":"2011","journal-title":"Cancers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev-physiol-021119-034627","article-title":"The Acidic Tumor Microenvironment as a Driver of Cancer","volume":"82","author":"Boedtkjer","year":"2020","journal-title":"Annu. Rev. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.4155\/tde.12.127","article-title":"Intelligent design of multifunctional lipid-coated nanoparticle platforms for cancer therapy","volume":"3","author":"Ramishetti","year":"2012","journal-title":"Ther. Deliv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.thorsurg.2018.12.001","article-title":"The Role of the Thymus in the Immune Response","volume":"29","author":"Thapa","year":"2019","journal-title":"Thorac. Surg. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.critrevonc.2007.04.005","article-title":"Management of thymomas","volume":"65","author":"Wright","year":"2008","journal-title":"Crit Rev. Oncol. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1111\/1759-7714.13053","article-title":"Alteration in gene expression profiles of thymoma: Genetic differences and potential novel targets","volume":"10","author":"Meng","year":"2019","journal-title":"Thorac. Cancer"},{"key":"ref_9","first-page":"2387","article-title":"Analysis of the tumor microen-vironment and mutation burden identifies prognostic features in thymic epithelial tumors","volume":"12","author":"Hou","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A scale for the quality assessment of narrative review articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e0182665","DOI":"10.1371\/journal.pone.0182665","article-title":"Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors","volume":"12","author":"Arbour","year":"2017","journal-title":"PLoS ONE"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8573","DOI":"10.1200\/JCO.2017.35.15_suppl.8573","article-title":"Pembrolizumab in patients with recurrent thymic carcinoma: Results of a phase II study","volume":"35","author":"Giaccone","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S1470-2045(18)30062-7","article-title":"Pembrolizumab in patients with thymic carcinoma: A single-arm, single-centre, phase 2 study","volume":"19","author":"Giaccone","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tateo, V., Manuzzi, L., De Giglio, A., Parisi, C., Lamberti, G., Campana, D., and Pantaleo, M. (2020). Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239056"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/PAI.0000000000000699","article-title":"Programmed Death-ligand 1 (PD-L1) Expression in Thymic Epithelial Tumors","volume":"28","author":"Bedekovics","year":"2020","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1097\/JTO.0000000000000429","article-title":"Diffuse High Intensity PD\u2013L1 Staining in Thymic Epithelial Tumors","volume":"10","author":"Padda","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.lungcan.2015.03.003","article-title":"Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma","volume":"88","author":"Katsuya","year":"2015","journal-title":"Lung Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4727","DOI":"10.1158\/1078-0432.CCR-16-0434","article-title":"Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma","volume":"22","author":"Yokoyama","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"BSR20220317","DOI":"10.1042\/BSR20220317","article-title":"Construction of immune-related LncRNAs classifier to predict prognosis and immunotherapy response in thymic epithelial tumors","volume":"42","author":"Su","year":"2022","journal-title":"Biosci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ejca.2019.03.012","article-title":"Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study","volume":"113","author":"Katsuya","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1200\/JCO.2017.77.3184","article-title":"Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial","volume":"37","author":"Cho","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1016\/j.athoracsur.2015.10.044","article-title":"Clinicopathologic and Prognostic Implications of Programmed Death Ligand 1 Expression in Thymoma","volume":"101","author":"Yokoyama","year":"2016","journal-title":"Ann. Thorac. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1177\/0300891620915788","article-title":"PD-L1 Ex-pression Level in Different Thymoma Stages and Thymic Carcinoma: A Meta-Analysis","volume":"106","author":"Chen","year":"2020","journal-title":"Tumori"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S1509","DOI":"10.21037\/jtd.2017.10.157","article-title":"Thymic tumors and immune checkpoint inhibitors","volume":"10","author":"Yokoyama","year":"2018","journal-title":"J. Thorac. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/modpathol.2017.6","article-title":"Expression of PD-1 and PD-L1 in thymic epithelial neoplasms","volume":"30","author":"Weissferdt","year":"2017","journal-title":"Mod. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/s40425-019-0723-9","article-title":"Efficacy and Tolerability of Anti-programmed Death-Ligand 1 (PD-L1) Antibody (Avelumab) Treatment in Advanced Thymoma","volume":"7","author":"Rajan","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Masaoutis, C., Palamaris, K., Kokkali, S., Levidou, G., and Theocharis, S. (2022). Unraveling the Immune Microenvironment of Thymic Epithelial Tumors: Implications for Autoimmunity and Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147864"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/BF02899268","article-title":"B-cells in thymic epithelial tumours","volume":"63","author":"Fend","year":"1993","journal-title":"Virchows Arch. B Cell Pathol. Incl. Mol. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1158\/0008-5472.CAN-11-0096","article-title":"Anti-TIM3 Antibody Promotes T Cell IFN-\u03b3\u2013Mediated Antitumor Immunity and Suppresses Established Tumors","volume":"71","author":"Ngiow","year":"2011","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1158\/1078-0432.CCR-16-2680","article-title":"Isolation of T-Cell Receptors Specifically Reactive with Mutated Tumor-Associated Antigens from Tumor-Infiltrating Lymphocytes Based on CD137 Ex-pression","volume":"23","author":"Parkhurst","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1080\/10408363.2020.1729692","article-title":"Immunoscore: A novel prognostic tool. Association with clinical outcome, response to treatment and survival in several malignancies","volume":"57","year":"2020","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mam.2014.05.001","article-title":"HMGB1 in health and disease","volume":"40","author":"Kang","year":"2014","journal-title":"Mol. Asp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Yang, Y., Xie, L., Li, C., Liu, L., Ye, X., and Han, J. (2022). Prognostic Model of Eleven Genes Based on the Immune Microenvironment in Patients With Thymoma. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.668696"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1111\/1759-7714.14002","article-title":"Significance of tumor mutation burden and immune infiltration in thymic epithelial tumors","volume":"12","author":"Wang","year":"2021","journal-title":"Thorac. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e000442","DOI":"10.1136\/esmoopen-2018-000442","article-title":"Imple-menting TMB measurement in clinical practice: Considerations on assay requirements","volume":"4","author":"Buttner","year":"2019","journal-title":"ESMO Open"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3892\/ijo.2014.2399","article-title":"HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (Review)","volume":"45","author":"Wang","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1111\/cas.14409","article-title":"CD20 + Tumor-infiltrating Immune Cells and CD204 + M2 Macrophages Are Associated with Prognosis in Thymic Carcinoma","volume":"111","author":"Sato","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/nri978","article-title":"Alternative activation of macrophages","volume":"3","author":"Gordon","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5278","DOI":"10.1158\/0008-5472.CAN-04-1853","article-title":"Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1\/epidermal growth factor paracrine loop","volume":"65","author":"Goswami","year":"2005","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/(SICI)1097-0215(19990219)84:1<74::AID-IJC14>3.0.CO;2-I","article-title":"Differing expression of MMPs-1 and -9 and urokinase receptor between diffuse- and intestinal-type gastric carcinoma","volume":"84","author":"Migita","year":"1999","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20304","DOI":"10.1038\/s41598-019-56835-8","article-title":"Adipose-derived mesenchymal stromal cells modulate lipid metabolism and lipid droplet biogenesis via AKT\/mTOR -PPARgamma Signalling in macrophages","volume":"9","author":"Soares","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1158\/0008-5472.CAN-11-2684","article-title":"Macrophage-induced tumor angiogenesis is reg-ulated by the TSC2-mTOR pathway","volume":"72","author":"Chen","year":"2012","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/BF02048033","article-title":"Heat shock protein 70 and HLA-DR molecules tissue expression","volume":"38","author":"Lazaris","year":"1995","journal-title":"Dis. Colon Rectum"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1111\/j.1600-0463.2008.01051.x","article-title":"Heat shock proteins 27, 60 and 70 as prognostic markers of prostate cancer","volume":"116","author":"Glaessgen","year":"2008","journal-title":"Apmis"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3346\/jkms.2005.20.5.829","article-title":"Expressions of HSP70 and HSP27 in Hepatocellular Carcinoma","volume":"20","author":"Joo","year":"2005","journal-title":"J. Korean Med Sci."},{"key":"ref_47","first-page":"501","article-title":"Stress proteins HSP27 and HSP70i predict survival in non-small cell lung carcinoma","volume":"28","author":"Gawrychowski","year":"2008","journal-title":"Anticancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"730","DOI":"10.4317\/medoral.17007","article-title":"The expression of heat shock proteins 27 and 105 in squamous cell carci-noma of the tongue and relationship with clinicopathological index","volume":"16","author":"Mohtasham","year":"2011","journal-title":"Med. Oral. Pathol. Oral. Cir. Bucal."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"24267","DOI":"10.1038\/srep24267","article-title":"HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: Diagnostic, prognostic and physiologic implications","volume":"6","author":"Janik","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/j.bmcl.2013.02.014","article-title":"Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets","volume":"23","author":"McConnell","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1053\/j.seminoncol.2019.08.002","article-title":"Fibronectin in malignancy: Cancer-specific alterations, protumoral effects, and therapeutic implications","volume":"46","author":"Rick","year":"2019","journal-title":"Semin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1517\/14728222.9.3.491","article-title":"ED-B fibronectin as a target for antibody-based cancer treatments","volume":"9","author":"Menrad","year":"2005","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Petrini, I., Sollini, M., Bartoli, F., Barachini, S., Montali, M., Pardini, E., Burzi, I.S., and Erba, P.A. (2022). ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach. Cancers, 14.","DOI":"10.3390\/cancers14112592"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Yuan, X., Huang, L., Luo, W., Zhao, Y., Nashan, B., Yu, F., and Liu, Y. (2021). Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.708735"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.semcancer.2019.03.004","article-title":"The role of SOX family members in solid tumours and metastasis","volume":"67","author":"Grimm","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"188517","DOI":"10.1016\/j.bbcan.2021.188517","article-title":"SOX9: An emerging driving factor from cancer progression to drug resistance","volume":"1875","author":"Panda","year":"2021","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1158\/0008-5472.CAN-11-3660","article-title":"Oncogenicity of the Developmental Transcription Factor Sox9","volume":"72","author":"Matheu","year":"2012","journal-title":"Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature03096","article-title":"Stromal fibroblasts in cancer initiation and progression","volume":"432","author":"Bhowmick","year":"2004","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/35025220","article-title":"Angiogenesis in cancer and other diseases","volume":"407","author":"Carmeliet","year":"2000","journal-title":"Nature"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/24\/6082\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:37:49Z","timestamp":1760146669000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/24\/6082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,10]]},"references-count":59,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["cancers14246082"],"URL":"https:\/\/doi.org\/10.3390\/cancers14246082","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,10]]}}}