{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:55:15Z","timestamp":1776142515293,"version":"3.50.1"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Tumor-associated macrophages (TAMs) are known to facilitate cancer progression. However, the diversity of TAM subsets and their distinct roles in GC remain poorly understood. This study aimed to evaluate the impact of legumain (LGMN)\n                      <jats:sup>+<\/jats:sup>\n                      macrophages on GC progression and clarify the underlying mechanisms of their roles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We used single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) analyses from public databases (GEO and TCGA) to systematically evaluate the clinical prognostic significance of LGMN and to characterize the remodeling of its associated signaling pathways. To investigate the role of LGMN in mouse GC (TAMs), we generated macrophage-specific LGMN conditional knockout mice, LGMN\n                      <jats:sup>flox\/flox<\/jats:sup>\n                      ;\n                      <jats:italic>Lyz2-Cre<\/jats:italic>\n                      . Utilizing a combination of subcutaneous xenograft tumor models, primary cell isolation and culture, immunofluorescence staining, and tube formation assays, we systematically elucidated the regulatory function and underlying molecular mechanisms of LGMN\n                      <jats:sup>+<\/jats:sup>\n                      macrophages in GC progression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that LGMN\n                      <jats:sup>+<\/jats:sup>\n                      macrophages are significantly enriched in GC tissues, and their high infiltration was significantly associated with poor outcomes. Additionally, scRNA-seq revealed that hypoxia and immune suppression pathways are enriched in LGMN\n                      <jats:sup>+<\/jats:sup>\n                      macrophages. LGMN\n                      <jats:sup>+<\/jats:sup>\n                      macrophages infiltration levels showed a significant positive correlation with the infiltration of regulatory T (Treg) cells and endothelial cells. Mechanistically, conditional knockout of LGMN in macrophages inhibits tumor growth by reprogramming TAMs toward an anti-tumor phenotype, reducing Treg cell infiltration, and enhancing the infiltration level of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Furthermore, LGMN knockout can inhibit tumor angiogenesis by downregulating VEGF-A expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      LGMN\n                      <jats:sup>+<\/jats:sup>\n                      macrophages drive GC progression by promoting tumor angiogenesis and establishing an immunosuppressive microenvironment. Therefore, targeting this TAM subset may represent a novel therapeutic strategy for GC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1810794","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:21:05Z","timestamp":1776140465000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["LGMN+ macrophage promotes the formation of a tumor-supportive microenvironment in gastric cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Weixin","family":"Zhang","sequence":"first","affiliation":[{"name":"First Central Hospital of Tianjin Medical University, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dapeng","family":"Chen","sequence":"additional","affiliation":[{"name":"First Central Hospital of Tianjin Medical University, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinming","family":"Li","sequence":"additional","affiliation":[{"name":"First Central Hospital of Tianjin Medical University, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianze","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Nankai University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengyu","family":"Jia","sequence":"additional","affiliation":[{"name":"First Central Hospital of Tianjin Medical University, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Tianjin First Central Hospital","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yamin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, Tianjin First Central Hospital","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s13045-023-01451-3","article-title":"Gastric cancer treatment: recent progress and future perspectives","volume":"16","author":"Guan","year":"2023","journal-title":"J Hematol Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-020-09925-3","article-title":"Gastric cancer: a comprehensive review of current and future treatment strategies","volume":"39","author":"Sexton","year":"2020","journal-title":"Cancer Metastasis Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188615","article-title":"Advances in clinical immunotherapy for gastric cancer","volume":"1876","author":"Li","year":"2021","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00789-4","article-title":"Antigen presentation in cancer - mechanisms and clinical implications for immunotherapy","volume":"20","author":"Yang","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.3370","article-title":"Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial","volume":"6","author":"Shitara","year":"2020","journal-title":"JAMA Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-17-0025","article-title":"Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced\/metastatic gastric or gastroesophageal junction cancer","volume":"23","author":"Bang","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.00892","article-title":"Phase III trial of avelumab maintenance after first-line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: Results from JAVELIN Gastric 100","volume":"39","author":"Moehler","year":"2021","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/bf02174042","article-title":"Families and clans of cysteine peptidases","volume":"6","author":"Barrett","year":"1996","journal-title":"Perspect Drug Discov Des"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.12.8090","article-title":"Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase","volume":"272","author":"Chen","year":"1997","journal-title":"J Biol Chem"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101238","article-title":"Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma","volume":"4","author":"Pang","year":"2023","journal-title":"Cell Rep Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/ph17070951","article-title":"Cancer cell secreted legumain\u00a0promotes gastric cancer resistance to anti-PD-1 immunotherapy by enhancing macrophage M2 polarization","volume":"17","author":"Pei","year":"2024","journal-title":"Pharm (Basel)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.36467","article-title":"Legumain promotes gastric cancer progression through tumor-associated macrophages in vitro and in vivo","volume":"16","author":"Wang","year":"2020","journal-title":"Int J Biol Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-21-0683","article-title":"Single-cell atlas of lineage states, tumor microenvironment, and subtype-specific expression programs in gastric cancer","volume":"12","author":"Kumar","year":"2022","journal-title":"Cancer Discov"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000676","article-title":"Oncogenic pathway combinations predict clinical prognosis in gastric cancer","volume":"5","author":"Ooi","year":"2009","journal-title":"PloS Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090133","article-title":"Nanostring-based multigene assay to predict recurrence for gastric cancer patients after surgery","volume":"9","author":"Lee","year":"2014","journal-title":"PloS One"},{"key":"B17","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"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-cell reconstruction of the early maternal-fetal interface in humans","volume":"563","author":"Vento-Tormo","year":"2018","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1023\/a:1008942828960","article-title":"Conditional gene targeting in macrophages and granulocytes using LysMcre mice","volume":"8","author":"Clausen","year":"1999","journal-title":"Transgenic Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.jim.2014.05.009","article-title":"Comparative analysis of the efficiency and specificity of myeloid-Cre deleting strains using ROSA-EYFP reporter mice","volume":"408","author":"Abram","year":"2014","journal-title":"J Immunol Methods"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13569","article-title":"Established gastric cancer cell lines transplantable into C57BL\/6 mice show fibroblast growth factor receptor 4 promotion of tumor growth","volume":"109","author":"Yamamoto","year":"2018","journal-title":"Cancer Sci"},{"key":"B23","doi-asserted-by":"publisher","first-page":"6783","DOI":"10.1016\/j.cell.2024.10.036","article-title":"Streptococcus anginosus promotes gastric inflammation, atrophy, and tumorigenesis in mice","volume":"187","author":"Fu","year":"2024","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1016\/j.cmet.2024.05.013","article-title":"Nicotinamide metabolism face-off between macrophages and fibroblasts manipulates the microenvironment in gastric cancer","volume":"36","author":"Jiang","year":"2024","journal-title":"Cell Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.nano.2011.03.001","article-title":"Synthetic enzyme inhibitor: a novel targeting ligand for nanotherapeutic drug delivery inhibiting tumor growth without systemic toxicity","volume":"7","author":"Liao","year":"2011","journal-title":"Nanomedicine"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-associated macrophages as treatment targets in oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2016.10.016","article-title":"Hypoxia-inducible factors: master regulators of cancer progression","volume":"2","author":"Schito","year":"2016","journal-title":"Trends Cancer"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3109\/10428199809058363","article-title":"Suppression of proliferation and phosphorylation of Jak3 and STAT5 in Malignant T-cell lymphoma cells by derivatives of octylamino-undecyl-dimethylxanthine","volume":"28","author":"Wasik","year":"1998","journal-title":"Leuk Lymphoma"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-8-67","article-title":"STAT5 regulation of BCL10 parallels constitutive NFkappaB activation in lymphoid tumor cells","volume":"8","author":"Nagy","year":"2009","journal-title":"Mol Cancer"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3109\/07357907.2014.883526","article-title":"IL-2 enhances cervical cancer cells proliferation and JAK3\/STAT5 phosphorylation at low doses, while at high doses IL-2 has opposite effects","volume":"32","author":"Valle-Mendiola","year":"2014","journal-title":"Cancer Invest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.mct-21-0943","article-title":"Low-dose JAK3 inhibition improves antitumor T-cell immunity and immunotherapy efficacy","volume":"21","author":"Dammeijer","year":"2022","journal-title":"Mol Cancer Ther"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/9364365","article-title":"Morphine in combination with ketamine improves cervical cancer pain and suppresses immune function via the JAK3\/STAT5 pathway","volume":"2022","author":"Jiang","year":"2022","journal-title":"Pain Res Manag"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nm1093","article-title":"Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival","volume":"10","author":"Curiel","year":"2004","journal-title":"Nat Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2023.102629","article-title":"Regulatory T cells in gastric cancer: Key controllers from pathogenesis to therapy","volume":"120","author":"Negura","year":"2023","journal-title":"Cancer Treat Rev"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-025-00832-9","article-title":"Regulatory T cells in the tumour microenvironment","volume":"25","author":"Imianowski","year":"2025","journal-title":"Nat Rev Cancer"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002591","article-title":"Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies","volume":"9","author":"Nishikawa","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1387975","article-title":"Regulation of Treg cells by cytokine signaling and co-stimulatory molecules","volume":"15","author":"Zong","year":"2024","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190418","article-title":"Biology and therapeutic potential of interleukin-10","volume":"217","author":"Saraiva","year":"2020","journal-title":"J Exp Med"},{"key":"B39","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":"B40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.16.8761","article-title":"Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal","volume":"94","author":"Benjamin","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00631-w","article-title":"Biology and therapeutic targeting of vascular endothelial growth factor A","volume":"24","author":"P\u00e9rez-Guti\u00e9rrez","year":"2023","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-021-01270-w","article-title":"CAF promotes chemoresistance through NRP2 in gastric cancer","volume":"25","author":"Yang","year":"2022","journal-title":"Gastric Cancer"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-13-0081","article-title":"Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy","volume":"19","author":"Kienast","year":"2013","journal-title":"Clin Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-00974-6","article-title":"The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention","volume":"20","author":"Cambier","year":"2023","journal-title":"Cell Mol Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6700750","article-title":"Endothelin-1: a multifunctional molecule in cancer","volume":"88","author":"Grant","year":"2003","journal-title":"Br J Cancer"},{"key":"B46","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.immuni.2014.06.010","article-title":"Tumor-associated macrophages: from mechanisms to therapy","volume":"41","author":"Noy","year":"2014","journal-title":"Immunity"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01084","article-title":"Macrophage polarization: Different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages","volume":"10","author":"Orecchioni","year":"2019","journal-title":"Front Immunol"},{"key":"B48","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"},{"key":"B49","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cell.2010.03.014","article-title":"Macrophage diversity enhances tumor progression and metastasis","volume":"141","author":"Qian","year":"2010","journal-title":"Cell"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-022-00675-6","article-title":"Macrophage functional diversity in NAFLD - more than inflammation","volume":"18","author":"Barreby","year":"2022","journal-title":"Nat Rev Endocrinol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.ejca.2014.10.020","article-title":"High expression of the cysteine proteinase legumain in colorectal cancer - implications for therapeutic targeting","volume":"51","author":"Haugen","year":"2015","journal-title":"Eur J Cancer"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10549-006-9311-z","article-title":"Legumain expression as a prognostic factor in breast cancer patients","volume":"102","author":"Gawenda","year":"2007","journal-title":"Breast Cancer Res Treat"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24143","article-title":"Legumain: a biomarker for diagnosis and prognosis of human ovarian cancer","volume":"113","author":"Wang","year":"2012","journal-title":"J Cell Biochem"},{"key":"B54","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/s41573-022-00520-5","article-title":"Macrophages as tools and targets in cancer therapy","volume":"21","author":"Mantovani","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.59.4358","article-title":"Immune checkpoint blockade in cancer therapy","volume":"33","author":"Postow","year":"2015","journal-title":"J Clin Oncol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune checkpoint blockade: a common denominator approach to cancer therapy","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065x.2011.01007.x","article-title":"Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication","volume":"241","author":"Quezada","year":"2011","journal-title":"Immunol Rev"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2015.02.003","article-title":"The interplay of effector and regulatory T cells in cancer","volume":"33","author":"Roychoudhuri","year":"2015","journal-title":"Curr Opin Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.702726","article-title":"Regulatory T cells: Barriers of immune infiltration into the tumor microenvironment","volume":"12","author":"Scott","year":"2021","journal-title":"Front Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.05.017","article-title":"Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer","volume":"44","author":"Perrone","year":"2008","journal-title":"Eur J Cancer"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0343-4","article-title":"Immune checkpoint signaling and cancer immunotherapy","volume":"30","author":"He","year":"2020","journal-title":"Cell Res"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-006433","article-title":"Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy","volume":"11","author":"van Elsas","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2025.101611","article-title":"Endothelial cell in tumor angiogenesis: Origins, mechanisms, and therapeutic implication","volume":"12","author":"Han","year":"2025","journal-title":"Genes Dis"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-021-00602-3","article-title":"Angiogenesis as a hallmark of solid tumors - clinical perspectives","volume":"44","author":"Majidpoor","year":"2021","journal-title":"Cell Oncol (Dordr)"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2018.29","article-title":"Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges","volume":"15","author":"Fukumura","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"key":"B66","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/s41392-023-01460-1","article-title":"Angiogenic signaling pathways and anti-angiogenic therapy for cancer","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-022-09863-4","article-title":"Proinflammatory activity of VEGF-targeted treatment through reversal of tumor endothelial cell anergy","volume":"26","author":"Nowak-Sliwinska","year":"2023","journal-title":"Angiogenesis"},{"key":"B68","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"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1810794\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:21:06Z","timestamp":1776140466000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1810794\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":68,"alternative-id":["10.3389\/fimmu.2026.1810794"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1810794","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"article-number":"1810794"}}