{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T03:28:58Z","timestamp":1786591738435,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,10]]},"group-title":"Cancer Biology","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"crossref","award":["W81XWH-22-1-0530"],"award-info":[{"award-number":["W81XWH-22-1-0530"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30CA016058"],"award-info":[{"award-number":["P30CA016058"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Ohio State University Klotz Chair Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Dedifferentiated liposarcoma (DDLPS) is characterized by abundant immune cell infiltration yet derives limited benefit from immune checkpoint blockade and stimulator of interferon genes (STING) agonist-based strategies, suggesting tumor-mediated suppression of antitumor immunity. Tumor-associated macrophages are the most abundant immune populations in DDLPS, but the factors regulating their function remain incompletely understood.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Extracellular vesicles (EVs) were isolated from two DDLPS cell lines and serum from 16 DDLPS patients and 13 healthy donors. EVs\u2019 impact on cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) -induced macrophage activation was assessed by cytokine secretion, surface markers, functional assays and macrophage-T-cell coculture. Proteomics was performed in EV-treated and EV-untreated macrophages from three donors. Pathway and protein interaction analyses were integrated with The Cancer Genome Atlas (TCGA) DDLPS transcriptomic and survival data.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We show that EVs released by DDLPS cells suppress macrophage responsiveness to classic STING agonist cGAMP. EVs derived from DDLPS attenuated cGAMP-induced expression of type I interferon-associated cytokines and chemokines, reduced IFN-\u03b2 secretion, and impaired phosphorylation of STING, TBK1 and IRF3. Functionally, DDLPS EV exposure shifted macrophages toward an immunoregulatory phenotype, restrained phagocytic activity, and attenuated macrophage-dependent T-cell proliferation while promoting T-cell exhaustion. Proteomic profiling revealed extensive macrophage reprogramming characterized by suppression of STING-associated signaling, antigen processing and presentation associated pathways and proteins targeted by miR-16-5p. Consistent with these findings, STING expression was associated with prolonged overall survival in DDLPS, while reduced expression of miR-16-5p target proteins was associated with attenuated STING pathway activity and immunostimulatory macrophage signatures.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings identify EV-mediated suppression of macrophage STING signaling as a mechanism of immune dysfunction in DDLPS and provide a framework for understanding immune resistance in this disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.07.743624","type":"posted-content","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:45:18Z","timestamp":1786376718000},"source":"Crossref","is-referenced-by-count":0,"title":["Extracellular vesicle-mediated suppression of macrophage STING signaling promotes immune dysfunction in dedifferentiated liposarcoma"],"prefix":"10.64898","author":[{"given":"Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA"},{"name":"Department of Retroperitoneal and Soft Tissue Surgical Oncology, Zhongshan Hospital, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay K","family":"Mandula","sequence":"additional","affiliation":[{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James Cancer Center and Solove Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Sarchet","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Dhawale","sequence":"additional","affiliation":[{"name":"The Ohio State University College of Arts and Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda C. C.","family":"de Faria","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Zhang","sequence":"additional","affiliation":[{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James Cancer Center and Solove Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Rentsch","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Premanshu K","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering, The Ohio State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali F","family":"Usmani","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering, The Ohio State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roma","family":"Karna","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor P","family":"Harper","sequence":"additional","affiliation":[{"name":"The Ohio State University College of Arts and Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Grignol","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Retroperitoneal and Soft Tissue Surgical Oncology, Zhongshan Hospital, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihai","family":"Li","sequence":"additional","affiliation":[{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-James Cancer Center and Solove Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael E","family":"Pollock","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Oncology, The James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Calore","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081219551288000_2026.08.07.743624v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21605"},{"key":"2026081219551288000_2026.08.07.743624v1.2","doi-asserted-by":"crossref","unstructured":"Schmitz E , Nessim C . 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