{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:11:01Z","timestamp":1785431461127,"version":"3.56.0"},"reference-count":91,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n","doi-asserted-by":"crossref","award":["FOSSIS A3-S-54604"],"award-info":[{"award-number":["FOSSIS A3-S-54604"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"crossref"}]},{"award":["FOSSIS A3-S-54604"],"award-info":[{"award-number":["FOSSIS A3-S-54604"]}],"id":[{"id":"https:\/\/ror.org\/059ex5q34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Soft tissue sarcomas are rare, biologically diverse mesenchymal malignancies in which pharmacologic resistance cannot be explained by a single unifying mechanism. In this narrative review, resistance is conceptualized as a dynamic, multilayered process shaped by histologic subtype, genomic architecture, transcriptional plasticity, the tumor microenvironment, and treatment-driven selective pressure. Resistance to conventional chemotherapy arises through both intrinsic and acquired mechanisms, including altered drug transport and metabolism, enhanced DNA damage responses, impaired apoptotic signaling, clonal selection, and the emergence of therapy-persistent cellular states. By contrast, resistance to targeted and epigenetic therapies more often reflects adaptive bypass signaling, lineage reprogramming, and incomplete identification of subtype-specific dependencies than secondary on-target alterations alone. The tumor microenvironment further contributes to therapeutic failure through hypoxia, extracellular matrix-mediated barriers, abnormal vascularization, myeloid-dominant immunosuppression, and immune exclusion, thereby helping explain the modest and histology-dependent activity of immune checkpoint inhibitors in soft tissue sarcoma. This review also differentiates baseline predictive biomarkers from dynamic resistance-monitoring tools, underscoring the potential\u2014despite still limited clinical maturity\u2014of pharmacogenomic markers, immune signatures, tertiary lymphoid structures, circulating tumor DNA, and circulating methylation-based approaches. Finally, emerging strategies to overcome resistance are examined, including mechanism-based combinations, biomarker-guided treatment selection, synthetic lethality, functional precision platforms, and adaptive histology-specific trial designs. Collectively, these observations support a view of resistance in soft tissue sarcoma as a context-dependent biological process that demands integrated, subtype-aware, and translationally grounded therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cancers18142364","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:01:28Z","timestamp":1784768488000},"page":"2364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacologic Resistance in Soft Tissue Sarcomas: Mechanisms, Biomarkers, and Translational Therapeutic Strategies"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1302-2896","authenticated-orcid":false,"given":"Dorian Yarih","family":"Garc\u00eda-Ortega","sequence":"first","affiliation":[{"name":"Departamento de Cirug\u00eda Oncol\u00f3gica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6957-2336","authenticated-orcid":false,"given":"Gabriela","family":"Alamilla-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Oncolog\u00eda M\u00e9dica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3310-1887","authenticated-orcid":false,"given":"Kevin Fernando","family":"Reyna-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Departamento de Oncolog\u00eda M\u00e9dica, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Baldriche-Acosta","sequence":"additional","affiliation":[{"name":"Secretar\u00eda del Medio Ambiente de la Ciudad de M\u00e9xico (SEDEMA), Ciudad de Mexico 06060, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3998-9306","authenticated-orcid":false,"given":"Luis Alonso","family":"Herrera-Montalvo","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Ciudad de Mexico 14250, Mexico"},{"name":"Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Ciudad de Mexico 14380, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5516-6081","authenticated-orcid":false,"given":"Carlo C\u00e9sar","family":"Cort\u00e9s-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Biom\u00e9dica en C\u00e1ncer, Instituto Nacional de Cancerolog\u00eda, Ciudad de Mexico 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref_1","first-page":"200","article-title":"Soft-tissue sarcoma in adults: An update on the current state of histotype-specific management in an era of personalized medicine","volume":"70","author":"Gamboa","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1016\/j.annonc.2021.07.006","article-title":"Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"32","author":"Gronchi","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S1470-2045(14)70063-4","article-title":"Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: A randomised controlled phase 3 trial","volume":"15","author":"Judson","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/S1470-2045(17)30622-8","article-title":"Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): A randomised controlled phase 3 trial","volume":"18","author":"Seddon","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1016\/S0140-6736(12)60651-5","article-title":"Pazopanib for metastatic soft-tissue sarcoma (PALETTE): A randomised, double-blind, placebo-controlled phase 3 trial","volume":"379","author":"Blay","year":"2012","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1001\/jama.2020.1707","article-title":"Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients with Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial","volume":"323","author":"Tap","year":"2020","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s11523-025-01145-5","article-title":"Potential Mechanisms for Immunotherapy Resistance in Adult Soft-Tissue Sarcoma","volume":"20","author":"Kret","year":"2025","journal-title":"Target. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.annonc.2021.09.005","article-title":"Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"33","author":"Casali","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1016\/j.cell.2017.10.014","article-title":"Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas","volume":"171","author":"Lazar","year":"2017","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1200\/JCO.2017.74.9374","article-title":"Contemporary Sarcoma Diagnosis, Genetics, and Genomics","volume":"36","author":"Schaefer","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Vibert, J., and Watson, S. (2022). The Molecular Biology of Soft Tissue Sarcomas: Current Knowledge and Future Perspectives. Cancers, 14.","DOI":"10.3390\/cancers14102548"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.ccell.2018.05.002","article-title":"The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma","volume":"33","author":"McBride","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1186\/s12967-024-05211-w","article-title":"Deciphering the role of FUS::DDIT3 expression and tumor microenvironment in myxoid liposarcoma development","volume":"22","author":"Ranji","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/gcc.20191","article-title":"Intratumor versus intertumor heterogeneity in gene expression profiles of soft-tissue sarcomas","volume":"43","author":"Francis","year":"2005","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1038\/s41467-018-06098-0","article-title":"Different patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years","volume":"9","author":"Hofvander","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Delgado, P., Lacerenza, S., Obrador-Hevia, A., Lopez-Alvarez, M., Mondaza-Hernandez, J.L., Blanco-Alcaina, E., Sanchez-Bustos, P., Hindi, N., Moura, D.S., and Martin-Broto, J. (2020). Cancer Stem Cells in Soft-Tissue Sarcomas. Cells, 9.","DOI":"10.3390\/cells9061449"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e004190","DOI":"10.1136\/jitc-2021-004190","article-title":"Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy","volume":"10","author":"Campbell","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1038\/s41374-019-0263-4","article-title":"Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology","volume":"99","author":"Kim","year":"2019","journal-title":"Lab. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Aiyer, S., Kim, T.-H., Collier, K., Pollock, R., Verschraegen, C., Stover, D.G., and Tinoco, G. (2025). Unlocking the potential of ctDNA in sarcomas: A review of recent advances. Cancers, 17.","DOI":"10.3390\/cancers17061040"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00402-024-05711-w","article-title":"Precision medicine in diagnosis, prognosis, and disease monitoring of bone and soft tissue sarcomas using liquid biopsy: A systematic review","volume":"145","author":"Smolle","year":"2025","journal-title":"Arch. Orthop. Trauma Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/S1470-2045(20)30451-4","article-title":"Tazemetostat in advanced epithelioid sarcoma with loss of INI1\/SMARCB1: An international, open-label, phase 2 basket study","volume":"21","author":"Gounder","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115727","DOI":"10.1016\/j.bcp.2023.115727","article-title":"Targeting EZH2 in SMARCB1-deficient sarcomas: Advances and opportunities to potentiate the efficacy of EZH2 inhibitors","volume":"215","author":"Lanzi","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1158\/2159-8290.CD-23-0110","article-title":"Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy","volume":"14","author":"Kazansky","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Roulleaux Dugage, M., Nassif, E.F., Italiano, A., and Bahleda, R. (2021). Improving immunotherapy efficacy in soft-tissue sarcomas: A biomarker-driven and histotype-tailored review. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.775761"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Fazel, M., Dufresne, A., Vanacker, H., Waissi, W., Blay, J.-Y., and Brahmi, M. (2023). Immunotherapy for soft tissue sarcomas: Anti-PD-1\/PD-L1 and beyond. Cancers, 15.","DOI":"10.3390\/cancers15061643"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/S1470-2045(17)30624-1","article-title":"Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial","volume":"18","author":"Tawbi","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S1470-2045(18)30006-8","article-title":"Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): Two open-label, non-comparative, randomised, phase 2 trials","volume":"19","author":"Mahoney","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1158\/1078-0432.CCR-19-1824","article-title":"Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab","volume":"26","author":"Keung","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1792036","DOI":"10.1080\/2162402X.2020.1792036","article-title":"Specific immune landscapes and immune checkpoint expressions in histotypes and molecular subtypes of sarcoma","volume":"9","author":"Dufresne","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"556","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"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Albertsmeier, M., Altendorf-Hofmann, A., Lindner, L.H., Issels, R.D., Kampmann, E., D\u00fcrr, H.R., Angele, M.K., Klauschen, F., Werner, J., and Jungbluth, A.A. (2022). VISTA in Soft Tissue Sarcomas: A Perspective for Immunotherapy?. Cancers, 14.","DOI":"10.3390\/cancers14041006"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e003687","DOI":"10.1136\/jitc-2021-003687","article-title":"Immunologic constant of rejection signature is prognostic in soft-tissue sarcoma and refines the CINSARC signature","volume":"10","author":"Bertucci","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1038\/s41591-022-01821-3","article-title":"Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: A phase 2 PEMBROSARC trial cohort","volume":"28","author":"Italiano","year":"2022","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e70396","DOI":"10.1002\/ctm2.70396","article-title":"Cancer therapy resistance from a spatial-omics perspective","volume":"15","author":"Zhang","year":"2025","journal-title":"Clin. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","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":"ref_36","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.tips.2023.12.006","article-title":"Leveraging spatial omics for the development of precision sarcoma treatments","volume":"45","author":"Tu","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Caruso, C., and Garofalo, C. (2020). Pharmacogenomics Biomarkers of Soft Tissue Sarcoma Therapies. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00509"},{"key":"ref_38","first-page":"100528","article-title":"Pharmacogenomics of soft tissue sarcomas: New horizons to understand efficacy and toxicity","volume":"31","author":"Gambale","year":"2022","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1158\/1535-7163.MCT-21-0315","article-title":"Predictive Value of MRP-1 in Localized High-Risk Soft Tissue Sarcomas: A Translational Research Associated to ISG-STS 1001 Randomized Phase III Trial","volume":"20","author":"Moura","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1002\/cncr.22669","article-title":"Assessment of ifosfamide pharmacokinetics, toxicity, and relation to CYP3A4 activity as measured by the erythromycin breath test in patients with sarcoma","volume":"109","author":"Chugh","year":"2007","journal-title":"Cancer"},{"key":"ref_41","first-page":"1085","article-title":"Mutational signatures and mutable motifs in cancer genomes","volume":"19","author":"Rogozin","year":"2018","journal-title":"Brief. Bioinform."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1158\/1078-0432.CCR-25-2580","article-title":"Validation of a Seven-Gene Predictive SIGNature for the Efficacy of Immuno-Oncology PD-1 Inhibitors in Patients with Sarcoma","volume":"32","author":"Moura","year":"2026","journal-title":"Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3944","DOI":"10.1158\/1078-0432.CCR-25-0134","article-title":"Droplet Digital PCR Assay for Detection and Monitoring of Universally Methylated ctDNA in Patients with Sarcoma","volume":"31","author":"Ashton","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4556","DOI":"10.1158\/0008-5472.CAN-17-0032","article-title":"Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transition in Mesenchymal Tumors: A Paradox in Sarcomas","volume":"77","author":"Sannino","year":"2017","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41392-021-00647-8","article-title":"Molecular mechanisms underpinning sarcomas and implications for current and future therapy","volume":"6","author":"Damerell","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Skrzypek, K., Nieszporek, A., Badyra, B., Lasota, M., and Majka, M. (2020). SNAIL promotes metastatic behavior of rhabdomyosarcoma by increasing EZRIN and AKT expression and regulating microRNA networks. Cancers, 12.","DOI":"10.3390\/cancers12071870"},{"key":"ref_47","first-page":"478","article-title":"Slug signaling is up-regulated by CCL21\/CCR7 to induce EMT in human chondrosarcoma","volume":"32","author":"Li","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3846","DOI":"10.1158\/0008-5472.CAN-16-2984","article-title":"Exosome-Derived miR-25-3p and miR-92a-3p Stimulate Liposarcoma Progression","volume":"77","author":"Casadei","year":"2017","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4390","DOI":"10.1016\/j.biomaterials.2014.02.003","article-title":"Microvesicle-mediated delivery of transforming growth factor \u03b21 siRNA for the suppression of tumor growth in mice","volume":"35","author":"Zhang","year":"2014","journal-title":"Biomaterials"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1002\/cncr.25925","article-title":"ERCC5\/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma","volume":"117","author":"Italiano","year":"2011","journal-title":"Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1002\/1878-0261.12996","article-title":"A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin","volume":"15","author":"Moura","year":"2021","journal-title":"Mol. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Nakamura, T., and Sudo, A. (2022). The Role of Trabectedin in Soft Tissue Sarcoma. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.777872"},{"key":"ref_53","first-page":"S3","article-title":"ET-743: More than an innovative mechanism of action","volume":"13","author":"Scotto","year":"2002","journal-title":"Anticancer Drugs"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13045-024-01580-3","article-title":"New strategies in soft tissue sarcoma treatment","volume":"17","author":"Ghazzi","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Haibe, Y., Kreidieh, M., El Hajj, H., Khalifeh, I., Mukherji, D., Temraz, S., and Shamseddine, A. (2020). Resistance Mechanisms to Anti-angiogenic Therapies in Cancer. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00221"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1080\/14728222.2024.2306344","article-title":"Epigenetic determinants in soft tissue sarcomas: Molecular mechanisms and therapeutic targets","volume":"28","author":"Merlini","year":"2024","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5575444","DOI":"10.1155\/2021\/5575444","article-title":"Prospects for epigenetic targeted therapies of bone and soft-tissue sarcomas","volume":"2021","author":"Wang","year":"2021","journal-title":"Sarcoma"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13045-024-01650-6","article-title":"Recent advances in sarcoma therapy: New agents, strategies and predictive biomarkers","volume":"17","author":"Pan","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4095","DOI":"10.1158\/0008-5472.CAN-23-2729","article-title":"Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy","volume":"83","author":"Mukhopadhyay","year":"2023","journal-title":"Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1158\/2159-8290.CD-24-0177","article-title":"Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer","volume":"14","author":"Dilly","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1054\/bjoc.2001.1728","article-title":"Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations","volume":"84","author":"Nordsmark","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"541650","DOI":"10.1155\/2012\/541650","article-title":"Prognostic impacts of hypoxic markers in soft tissue sarcoma","volume":"2012","author":"Smeland","year":"2012","journal-title":"Sarcoma"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13045-021-01125-y","article-title":"Metabolic landscapes in sarcomas","volume":"14","author":"Miallot","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Pankova, D., Thway, K., Jones, R.L., and Huang, P.H. (2021). The extracellular matrix in soft tissue sarcomas: Pathobiology and cellular signalling. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.763640"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Raut, C.P., Boucher, Y., Duda, D.G., Morgan, J.A., Quek, R., Ancukiewicz, M., Lahdenranta, J., Eder, J.P., Demetri, G.D., and Jain, R.K. (2012). Effects of sorafenib on intra-tumoral interstitial fluid pressure and circulating biomarkers in patients with refractory sarcomas (NCI protocol 6948). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0026331"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1747340","DOI":"10.1080\/2162402X.2020.1747340","article-title":"Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas","volume":"9","author":"Dancsok","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4018","DOI":"10.1158\/1078-0432.CCR-19-3416","article-title":"The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures","volume":"26","author":"Chen","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1080\/0284186X.2023.2172688","article-title":"Immune-cell infiltration in high-grade soft tissue sarcomas; prognostic implications of tumor-associated macrophages and B-cells","volume":"62","author":"Nilbert","year":"2023","journal-title":"Acta Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Jumaniyazova, E., Lokhonina, A., Dzhalilova, D., Kosyreva, A., and Fatkhudinov, T. (2023). Immune cells in the tumor microenvironment of soft tissue sarcoma. Cancers, 15.","DOI":"10.3390\/cancers15245760"},{"key":"ref_70","first-page":"328","article-title":"Immune checkpoint inhibitor resistance in soft tissue sarcoma","volume":"5","author":"Eulo","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1002\/cbin.10603","article-title":"Mesenchymal stem cells: From stem cells to sarcomas","volume":"40","author":"Lye","year":"2016","journal-title":"Cell Biol. Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1002\/stem.1472","article-title":"Expression of FUS-CHOP fusion protein in immortalized\/transformed human mesenchymal stem cells drives mixoid liposarcoma formation","volume":"31","author":"Rodriguez","year":"2013","journal-title":"Stem Cells"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41698-021-00157-4","article-title":"Predictive and prognostic transcriptomic biomarkers in soft tissue sarcomas","volume":"5","author":"Merry","year":"2021","journal-title":"npj Precis. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00018-024-05250-y","article-title":"HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study","volume":"81","author":"Moura","year":"2024","journal-title":"Cell Mol. Life Sci."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Berclaz, L.M., Altendorf-Hofmann, A., D\u00fcrr, H.R., Klein, A., Angele, M.K., Albertsmeier, M., Schmidt-Hegemann, N.S., Di Gioia, D., Kn\u00f6sel, T., and Lindner, L.H. (2021). Expression Patterns of TOP2A and SIRT1 Are Predictive of Survival in Patients with High-Risk Soft Tissue Sarcomas Treated with a Neoadjuvant Anthracycline-Based Chemotherapy. Cancers, 13.","DOI":"10.3390\/cancers13194877"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/ijc.35477","article-title":"Blood-based biomarkers in soft tissue sarcoma: Implications for immune checkpoint inhibitor therapy","volume":"157","author":"Mannah","year":"2025","journal-title":"Int. J. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Mavroeidis, L., Napolitano, A., Huang, P.H., and Jones, R.L. (2025). Novel therapeutics in soft tissue sarcoma. Cancers, 17.","DOI":"10.3390\/cancers17010010"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6424","DOI":"10.1158\/1078-0432.CCR-21-2001","article-title":"Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma","volume":"27","author":"Livingston","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e001561","DOI":"10.1136\/jitc-2020-001561","article-title":"Nivolumab and sunitinib combination in advanced soft tissue sarcomas: A multicenter, single-arm, phase Ib\/II trial","volume":"8","author":"Hindi","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/s41467-024-44875-2","article-title":"Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: A phase II trial","volume":"15","author":"Cho","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1080\/14737140.2024.2384584","article-title":"Progress in histology-specific treatments in soft tissue sarcoma","volume":"24","author":"Radaelli","year":"2024","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"105837","DOI":"10.1016\/j.esmoop.2025.105837","article-title":"Expression of antibody-drug conjugate targets in soft tissue sarcomas","volume":"10","author":"Bertucci","year":"2025","journal-title":"ESMO Open"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Lynch, M.M., Al-Marayaty, R., Obeidin, F., Alexiev, B.A., Chen, E.Y., Viveiros, P., Schroeder, B.A., Hudkins, K., Fan, T.M., and Redman, M.W. (2024). B7-H3 is widely expressed in soft tissue sarcomas. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-13061-4"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.annonc.2025.11.019","article-title":"Trabectedin-olaparib combination or trabectedin in advanced soft tissue sarcomas after failure of anthracycline-based treatment (TOMAS2): A randomized phase II study from the Italian Sarcoma Group","volume":"37","author":"Merlini","year":"2026","journal-title":"Ann. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Italiano, A., Dinart, D., Soubeyran, I., Bellera, C., Esp\u00e9rou, H., Delmas, C., Mercier, N., Albert, S., Poignie, L., and Boland, A. (2021). Molecular profiling of advanced soft-tissue sarcomas: The MULTISARC randomized trial. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08878-2"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1007\/s00432-022-04149-0","article-title":"In search of effective therapies: The current landscape of phase II trials in patients with advanced soft tissue sarcoma","volume":"149","author":"Sobczuk","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ejca.2022.07.010","article-title":"New benchmarks to design clinical trials with advanced or metastatic liposarcoma or synovial sarcoma patients: An EORTC\u2014Soft Tissue and Bone Sarcoma Group (STBSG) meta-analysis based on a literature review for soft-tissue sarcomas","volume":"174","author":"Kantidakis","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"100425","DOI":"10.1016\/j.esmoop.2022.100425","article-title":"Early phase trials in soft-tissue sarcomas: Clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials","volume":"7","author":"Nassif","year":"2022","journal-title":"ESMO Open"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"123546","DOI":"10.1016\/j.biomaterials.2025.123546","article-title":"Generation of patient-derived sarcoma organoids for personalized drug screening and precision cancer immunotherapy","volume":"324","author":"Ma","year":"2026","journal-title":"Biomaterials"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Yarar, S., and Tsagkozis, P. (2025). Functional assays to guide personalized oncological treatment of patients with soft-tissue sarcomas. Cancers, 17.","DOI":"10.3390\/cancers17213452"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"100048","DOI":"10.1016\/j.esmorc.2025.100048","article-title":"ARTEMIS-002: A phase 2 study of hs-20093 in patients with relapsed or refractory sarcomas","volume":"4","author":"Xie","year":"2025","journal-title":"ESMO Rare Cancers"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:21:59Z","timestamp":1784866919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":91,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18142364"],"URL":"https:\/\/doi.org\/10.3390\/cancers18142364","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]}}}