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Immunol."],"abstract":"<jats:p>Myxofibrosarcoma (MFS) is a rare and aggressive soft tissue sarcoma characterized by high genomic instability, resulting in high local recurrence rates and limited effective therapeutic options in advanced stages. Recent progress in cancer immunology research has encouraged investigation into the Tumor Microenvironment (TME) of sarcomas, including MFS, to identify immune-related biomarkers of prognostic and therapeutic relevance. Although data remain limited in MFS, existing evidence suggests a heterogeneous immune landscape, including: i) variable expression of immune checkpoint molecules such as Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1), ii) presence of tumor-infiltrating lymphocytes, iii) alterations in antigen presentation pathways, and iv) a pronounced angiogenic signature. These findings underscore the potential role of immune biomarkers for patients\u2019 clinical stratification and the consequent possibility of developing new immunotherapeutic strategies. This review will focus on the cellular and molecular architecture of immune infiltration, vascular remodeling, and lymphoid neogenesis, assessing their prognostic and predictive value as potential biomarkers. Finally, we will present ongoing clinical trials aimed at modulating the immune-vascular niche to inform innovative therapeutic strategies for this challenging sarcoma subtype.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1717541","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T06:38:40Z","timestamp":1767595120000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Unveiling the myxofibrosarcoma tumor microenvironment: implications for immunotherapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Cecilia","family":"Profumo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Grassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Rigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Mascherini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Arcovito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Anselmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Damele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Timon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danila","family":"Comandini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Croce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"70","DOI":"10.32074\/1591-951X-213","article-title":"The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives","volume":"113","author":"Sbaraglia","year":"2020","journal-title":"Pathologica"},{"key":"B2","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":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0488-6","article-title":"The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications","volume":"17","author":"Zhang","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"17588359221093972","DOI":"10.1177\/17588359221093973","article-title":"Myxofibrosarcoma landscape: diagnostic pitfalls, clinical management and future perspectives","volume":"14","author":"Vanni","year":"2022","journal-title":"Ther Adv Med Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15215132","article-title":"Modeling myxofibrosarcoma: where do we stand and what is missing","volume":"15","author":"Lucarelli","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/1758834017737472","article-title":"Myxofibrosarcoma primary cultures: molecular and pharmacological profile","volume":"9","author":"De Vita","year":"2017","journal-title":"Ther Adv Med Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s13569-017-0082-6","article-title":"Activity of anthracycline- and ifosfamide-based chemotherapy in a series of patients affected by advanced myxofibrosarcoma","volume":"7","author":"Colia","year":"2017","journal-title":"Clin Sarcoma Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2004.01.016","article-title":"Low-grade myxofibrosarcoma: a clinicopathologic analysis of 49 cases treated at a single institution with simultaneous assessment of the efficacy of 3-tier and 4-tier grading systems","volume":"35","author":"Huang","year":"2004","journal-title":"Hum Pathol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1097\/00000478-199604000-00001","article-title":"Myxofibrosarcoma. 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