{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T05:44:57Z","timestamp":1785908697697,"version":"3.56.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Changes in the tumor microenvironment (TME) are closely involved in hepatocellular carcinoma (HCC) development, and lipid metabolic disorders may take part in this process. STARD3NL is known to be related to cholesterol trafficking and lipid homeostasis. However, little is known about whether STARD3NL is linked to immune features of the HCC microenvironment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We first explored STARD3NL expression and its prognostic relevance in HCC using The Cancer Genome Atlas (TCGA). To verify the bioinformatic findings, HCC tissue microarrays (TMAs) were analyzed by immunohistochemistry (IHC) for STARD3NL localization and survival evaluation. Multiplex immunohistochemistry (mIHC), combined with digital image analysis, was further used to characterize immune cell infiltration. Clinicopathological differences between tumors with high and low STARD3NL expression were also examined. In addition, spatial distance analysis was performed to assess how immune cells were arranged in STARD3NL-high regions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TCGA-based analysis and mIHC validation both showed higher STARD3NL expression in HCC tissues. Patients with increased STARD3NL expression had poorer survival (p = 0.029), and multivariable analysis supported STARD3NL as an independent risk factor. STARD3NL-high tumors showed increased proportions of CD68+ macrophages and FOXP3+ T cells (p &amp;lt; 0.005). Spatial analysis further indicated that Tregs were more frequently located near macrophages (p = 0.001), with a shorter mean macrophage-Treg distance (p = 0.027). This macrophage-Treg proximity was associated with worse prognosis (p = 0.030).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>High STARD3NL expression is significantly associated with immune-suppressive features and unfavorable outcomes in HCC. These findings indicate that STARD3NL may have value as a prognostic biomarker associated with an immunosuppressive tumor microenvironment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1911730","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:51:52Z","timestamp":1785905512000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["STARD3NL as a prognostic marker related to an immunosuppressive tumor microenvironment in hepatocellular carcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Di","family":"Li","sequence":"first","affiliation":[{"name":"New World Institute of Biotechnology, School of Biotechnology, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Discipline Construction Department, National Engineering Research Center for Biochip at Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Xie","sequence":"additional","affiliation":[{"name":"Discipline Construction Department, National Engineering Research Center for Biochip at Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[{"name":"Discipline Construction Department, National Engineering Research Center for Biochip at Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guocui","family":"Yang","sequence":"additional","affiliation":[{"name":"Discipline Construction Department, National Engineering Research Center for Biochip at Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyun","family":"Li","sequence":"additional","affiliation":[{"name":"Discipline Construction Department, National Engineering Research Center for Biochip at Shanghai","place":["Shanghai, China"]},{"name":"School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Qin","sequence":"additional","affiliation":[{"name":"Discipline Construction Department, National Engineering Research Center for Biochip at Shanghai","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinping","family":"Lin","sequence":"additional","affiliation":[{"name":"New World Institute of Biotechnology, School of Biotechnology, East China University of Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.jncc.2024.01.006","article-title":"Cancer incidence and mortality in China, 2022","volume":"4","author":"Han","year":"2024","journal-title":"J Natl Cancer Cent"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jncc.2022.02.002","article-title":"Cancer incidence and mortality in China, 2016","volume":"2","author":"Zheng","year":"2022","journal-title":"J Natl Cancer Cent"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)30427-1","article-title":"Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017","volume":"394","author":"Zhou","year":"2019","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1142168","article-title":"Predictive value of preoperative inflammatory indexes for postoperative early recurrence of hepatitis B-related hepatocellular carcinoma","volume":"13","author":"Wenpei","year":"2023","journal-title":"Front Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.21037\/hbsn-23-631","article-title":"Inflammatory indicators such as systemic immune inflammation index (SIII), systemic inflammatory response index (SIRI), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic factors of curative hepatic resections for hepatocellular carcinoma","volume":"13","author":"Gavriilidis","year":"2024","journal-title":"Hepatobiliary Surg Nutr"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.12.042","article-title":"Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma","volume":"144","author":"Zheng","year":"2013","journal-title":"Gastroenterology"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1808","article-title":"Therapeutic targeting of the tumor microenvironment","volume":"11","author":"Bejarano","year":"2021","journal-title":"Cancer Discov"},{"key":"B9","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1186\/s12929-022-00866-3","article-title":"Tumor microenvironment: barrier or opportunity towards effective cancer therapy","volume":"29","author":"Tiwari","year":"2022","journal-title":"J BioMed Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0337-2","article-title":"The future of cancer immunotherapy: microenvironment-targeting combinations","volume":"30","author":"Murciano-Goroff","year":"2020","journal-title":"Cell Res"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3686","DOI":"10.1016\/j.cell.2023.07.026","article-title":"Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin","volume":"186","author":"Ruf","year":"2023","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s12943-023-01725-x","article-title":"Roles of tumor-associated macrophages in anti-PD-1\/PD-L1 immunotherapy for solid cancers","volume":"22","author":"Zhang","year":"2023","journal-title":"Mol Cancer"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2023.07.015","article-title":"Modulating Treg stability to improve cancer immunotherapy","volume":"9","author":"Kang","year":"2023","journal-title":"Trends Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.01.011","article-title":"Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy","volume":"78","author":"Liu","year":"2023","journal-title":"J Hepatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13061461","article-title":"Metabolism and immune suppressive response in liver cancer","volume":"13","author":"Caini","year":"2025","journal-title":"Biomedicines"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1435480","article-title":"Lipids in the tumor microenvironment: immune modulation and metastasis","volume":"14","author":"Pascual","year":"2024","journal-title":"Front Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1639823","article-title":"The impact of aberrant lipid metabolism on the immune microenvironment of gastric cancer: a mini review","volume":"16","author":"Chen","year":"2025","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1579054","article-title":"Cholesterol effects on the tumor immune microenvironment: from fundamental concepts to mechanisms and implications","volume":"15","author":"Lagunas-Rangel","year":"2025","journal-title":"Front Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1042\/BST20150269","article-title":"Touch\u00e9! STARD3 and STARD3NL tether the ER to endosomes","volume":"44","author":"Wilhelm","year":"2016","journal-title":"Biochem Soc Trans"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.139295","article-title":"STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the ER","volume":"126","author":"Alpy","year":"2013","journal-title":"J Cell Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-2994","article-title":"Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages","volume":"80","author":"Su","year":"2020","journal-title":"Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-024-01199-x","article-title":"Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20\/CCR6 axis in human hepatocellular carcinoma","volume":"21","author":"Wang","year":"2024","journal-title":"Cell Mol Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2021.06.018","article-title":"Combining gene expression signature with clinical features for survival stratification of gastric cancer","volume":"113","author":"Sun","year":"2021","journal-title":"Genomics"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaf018","article-title":"edgeR v4: powerful differential analysis of sequencing data with expanded functionality and improved support for small counts and larger datasets","volume":"53","author":"Chen","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics J Integr Biol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1652","article-title":"Evaluation of explant responses to STING ligands: personalized immunosurgical therapy for head and neck squamous cell carcinoma","volume":"78","author":"Baird","year":"2018","journal-title":"Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1038\/s41467-024-46450-1","article-title":"Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors","volume":"15","author":"Gil-Jimenez","year":"2024","journal-title":"Nat Commun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001813","article-title":"Tumor-infiltrating plasmacytoid dendritic cells are associated with survival in human colon cancer","volume":"9","author":"Kie\u00dfler","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13184693","article-title":"STARD3: a prospective target for cancer therapy","volume":"13","author":"Asif","year":"2021","journal-title":"Cancers"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0174-0","article-title":"Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities","volume":"2","author":"Huang","year":"2020","journal-title":"Nat Metab"},{"key":"B33","doi-asserted-by":"publisher","first-page":"6314","DOI":"10.1038\/s41467-021-26718-6","article-title":"N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism","volume":"12","author":"Wang","year":"2021","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.ccell.2020.08.015","article-title":"Cholesterol pathway inhibition induces TGF-\u03b2 signaling to promote basal differentiation in pancreatic cancer","volume":"38","author":"Gabitova-Cornell","year":"2020","journal-title":"Cancer Cell"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-022-00872-3","article-title":"Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver","volume":"19","author":"Tang","year":"2022","journal-title":"Cell Mol Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6594169","article-title":"Clinical implication and the hereditary factors of NM23 in hepatocellular carcinoma based on bioinformatics analysis and genome-wide association study","volume":"2018","author":"Yang","year":"2018","journal-title":"J Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.12182\/20210160202","article-title":"A review of the lipid metabolism reprogramming in tumor associated macrophages","volume":"52","author":"Zhao","year":"2021","journal-title":"J Sichuan Univ Med Sci Ed"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0127-6","article-title":"Macrophages as regulators of tumour immunity and immunotherapy","volume":"19","author":"DeNardo","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-012418-012718","article-title":"Diversity, mechanisms, and significance of macrophage plasticity","volume":"15","author":"Locati","year":"2020","journal-title":"Annu Rev Pathol Mech Dis"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0534-z","article-title":"Prognostic value of macrophage polarization markers in epithelial neoplasms and melanoma: a systematic review and meta-analysis","volume":"33","author":"L\u00f3pez-Janeiro","year":"2020","journal-title":"Mod Pathol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080908","article-title":"Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages","volume":"8","author":"Barros","year":"2013","journal-title":"PloS One"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01512","article-title":"Evaluating the polarization of tumor-associated macrophages into M1 and M2 phenotypes in human cancer tissue: technicalities and challenges in routine clinical practice","volume":"9","author":"Jayasingam","year":"2019","journal-title":"Front Oncol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn8608","article-title":"Platelet factor 4-induced TH1-Treg polarization suppresses antitumor immunity","volume":"386","author":"Kuratani","year":"2024","journal-title":"Science"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1911730\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:51:56Z","timestamp":1785905516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1911730\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":43,"alternative-id":["10.3389\/fonc.2026.1911730"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1911730","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]},"article-number":"1911730"}}