{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T06:04:32Z","timestamp":1771653872031,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PT20\/00004"],"award-info":[{"award-number":["PT20\/00004"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI21\/00869"],"award-info":[{"award-number":["PI21\/00869"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["CP20\/00106"],"award-info":[{"award-number":["CP20\/00106"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI21\/01178"],"award-info":[{"award-number":["PI21\/01178"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI24\/01106"],"award-info":[{"award-number":["PI24\/01106"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["CD25\/00102"],"award-info":[{"award-number":["CD25\/00102"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lung cancer remains the leading cause of cancer-related mortality worldwide and is frequently diagnosed at advanced stages, when metastatic dissemination is already present. Tumour hybrid cells (THCs) are rare circulating cells formed through fusion between cancer stem cells with leukocytes, predominantly monocytes. These cells combine traits from both lineages, conferring enhanced migratory, invasive and immune-evasive capacities that could promote metastasis. In parallel, soluble immune checkpoints (sICs) have emerged as minimally invasive biomarkers and indicators of systemic immune dysregulation and tumour-driven immune escape. In this study, 31 patients with lung cancer were prospectively enrolled at La Paz University Hospital (Madrid, Spain). Circulating THCs were quantified by spectral flow cytometry, and plasma sICs concentrations were determined using multiplex immunoassays. Patients were stratified by metastatic status and survival. Variables showing the strongest discriminative capacity were integrated into multivariable logistic regression models. Number of THCs, and levels of sCTLA-4, s-41BB, sLAG-3, and sTIM-3 exhibited the strongest discrimination for metastasis, while THCs, sLAG-3, and sTIM-3 distinguished deceased from surviving patients. Integrating predictive models demonstrated high accuracy, and survival analyses supported their prognostic significance. These findings indicate circulating THCs and selected sICs represent promising liquid biomarkers for monitoring lung cancer progression and patient outcomes.<\/jats:p>","DOI":"10.3390\/ijms27041994","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T13:47:02Z","timestamp":1771508822000},"page":"1994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Circulating Signature of Tumour Hybrid Cells and Immune Checkpoints Predicts Metastatic Progression in Lung Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Gonzalo","family":"S\u00e1enz de Santa Mar\u00eda-Diez","sequence":"first","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Liana Pardo-Prieto","sequence":"additional","affiliation":[{"name":"Thoracic Surgery Service, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0093-9707","authenticated-orcid":false,"given":"Roberto","family":"Lozano-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Urko","family":"Aguirre-Larracoechea","sequence":"additional","affiliation":[{"name":"Research Unit, Osakidetza Basque Health Service, Barrualde-Galdakao Integrated Health Organisation, Galdakao-Usansolo Hospital, 48960 Galdakao, Spain"},{"name":"Kronikgune Institute for Health 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IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1612-103X","authenticated-orcid":false,"given":"Karla","family":"Montalb\u00e1n-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Arvelo-Rosario","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas","family":"Fern\u00e1ndez-Felipe","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Faculty of Health Sciences, Campus Castellana, UNIE University, 28036 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"C\u00f3rdoba","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6546-3039","authenticated-orcid":false,"given":"Gloria C.","family":"Bonel-P\u00e9rez","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1771-7254","authenticated-orcid":false,"given":"Carlos","family":"del Fresno","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Hurtado-Navarro","sequence":"additional","affiliation":[{"name":"The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain"},{"name":"Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 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Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102693","DOI":"10.1016\/j.canep.2024.102693","article-title":"Global Burden of Lung Cancer in 2022 and Projections to 2050: Incidence and Mortality Estimates from GLOBOCAN","volume":"93","author":"Zhou","year":"2024","journal-title":"Cancer Epidemiol."},{"key":"ref_2","unstructured":"(2025, November 24). World Cancer Research\u2014Lung Cancer. Available online: https:\/\/www.wcrf.org\/preventing-cancer\/cancer-types\/lung-cancer\/#what-causes-lung-cancer."},{"key":"ref_3","first-page":"437","article-title":"Delays in the Diagnosis of Lung Cancer","volume":"39","author":"Barrueco","year":"2003","journal-title":"Arch. Bronconeumol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41392-020-0134-x","article-title":"Molecular Principles of Metastasis: A Hallmark of Cancer Revisited","volume":"5","author":"Fares","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Collazo, E., and Hurtado-Navarro, L. (2025). Cell Fusion as a Driver of Metastasis: Re-Evaluating an Old Hypothesis in the Age of Cancer Heterogeneity. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1524781"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1097\/PAP.0000000000000219","article-title":"Paget\u2019s \u201cSeed and Soil\u201d Theory of Cancer Metastasis: An Idea Whose Time Has Come","volume":"26","author":"Akhtar","year":"2019","journal-title":"Adv. Anat. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41586-018-0040-3","article-title":"Identification of the Tumour Transition States Occurring during EMT","volume":"556","author":"Pastushenko","year":"2018","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ceb.2016.06.002","article-title":"Epithelial-Mesenchymal Transition (EMT) and Metastasis: Yes, No, Maybe?","volume":"43","author":"Diepenbruck","year":"2016","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_9","unstructured":"Aichel, O. (1911). Vortr\u00e4ge Und Aufs\u00e4tze \u00dcber Entwickelungsmechanik Der Organismen. \u00dcber Zellverschmelzung mit Qualitativ Abnormer Chromosomenverteilung als Ursache der Geschwulstbildung, Wilhelm Engelmann."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Laberge, G.S., Duvall, E., Haedicke, K., and Pawelek, J. (2019). Leukocyte\u2013Cancer Cell Fusion\u2014Genesis of a Deadly Journey. Cells, 8.","DOI":"10.3390\/cells8020170"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Jiang, C., and Wu, J. (2024). Hypothesis: Hematogenous Metastatic Cancer Cells of Solid Tumors May Disguise Themselves as Memory Macrophages for Metastasis. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1412296"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7350","DOI":"10.1038\/s41598-024-57381-8","article-title":"Ultra High Content Analyses of Circulating and Tumor Associated Hybrid Cells Reveal Phenotypic Heterogeneity","volume":"14","author":"Whalen","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s40364-024-00609-6","article-title":"Detection of Neoplastic-Immune Hybrid Cells with Metastatic Properties in Uveal Melanoma","volume":"12","author":"Anderson","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"660","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":"ref_15","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.immuni.2024.02.001","article-title":"Interleukin-2 Signaling in the Regulation of T Cell Biology in Autoimmunity and Cancer","volume":"57","author":"Shouse","year":"2024","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e70196","DOI":"10.1002\/iid3.70196","article-title":"Immune Checkpoint Molecules: A Review on Pathways and Immunotherapy Implications","volume":"13","author":"Majidazar","year":"2025","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"116505","DOI":"10.1016\/j.trac.2021.116505","article-title":"Analytical Methods for the Detection of PD-1\/PD-L1 and Other Molecules Related to Immune Checkpoints","volume":"146","author":"Wang","year":"2022","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1016\/j.cell.2023.03.006","article-title":"Immune Checkpoint Therapy\u2014Current Perspectives and Future Directions","volume":"186","author":"Sharma","year":"2023","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Vicidomini, G. (2023). Current Challenges and Future Advances in Lung Cancer: Genetics, Instrumental Diagnosis and Treatment. Cancers, 15.","DOI":"10.3390\/cancers15143710"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12943-023-01740-y","article-title":"Lung Cancer Immunotherapy: Progress, Pitfalls, and Promises","volume":"22","author":"Lahiri","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"84559","DOI":"10.18632\/oncotarget.19187","article-title":"Novel Strategies to Prevent the Development of Multidrug Resistance (MDR) in Cancer","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_22","first-page":"560","article-title":"Immune Checkpoint Inhibitors in Clinical Practice: Update on Management of Immune-Related Toxicities","volume":"4","author":"Villadolid","year":"2015","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eabd2712","DOI":"10.1126\/sciadv.abd2712","article-title":"Revisiting the PD-1 Pathway","volume":"6","author":"Patsoukis","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s12943-024-02023-w","article-title":"Regulatory Mechanisms of PD-1\/PD-L1 in Cancers","volume":"23","author":"Lin","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e010612","DOI":"10.1136\/jitc-2024-010612","article-title":"Cell-Intrinsic PD-L1 Signaling Drives Immunosuppression by Myeloid-Derived Suppressor Cells through IL-6\/Jak\/Stat3 in PD-L1-High Lung Cancer","volume":"13","author":"Jeong","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_26","first-page":"727","article-title":"PD-1\/PD-L1 Pathway: Current Researches in Cancer","volume":"10","author":"Han","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.cllc.2017.02.004","article-title":"A Comprehensive Analysis of Programmed Cell Death Ligand-1 Expression with the Clone SP142 Antibody in Non\u2013Small-Cell Lung Cancer Patients","volume":"18","author":"Takada","year":"2017","journal-title":"Clin. Lung Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101831","DOI":"10.1016\/j.xcrm.2024.101831","article-title":"Analysis of PD1, LAG3, TIGIT, and TIM3 Expression in Human Lung Adenocarcinoma Reveals a 25-Gene Signature Predicting Immunotherapy Response","volume":"5","author":"Peyraud","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/s40425-019-0768-9","article-title":"The Role of PD-L1 Expression as a Predictive Biomarker: An Analysis of All US Food and Drug Administration (FDA) Approvals of Immune Checkpoint Inhibitors","volume":"7","author":"Davis","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Huo, J.-L., Wang, Y.-T., Fu, W.-J., Lu, N., and Liu, Z.-S. (2022). The Promising Immune Checkpoint LAG-3 in Cancer Immunotherapy: From Basic Research to Clinical Application. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.956090"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sauer, N., Szlasa, W., Jonderko, L., O\u015bliz\u0142o, M., Kunachowicz, D., Kulbacka, J., and Kar\u0142owicz-Bodalska, K. (2022). LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23179958"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e001014","DOI":"10.1136\/jitc-2020-001014","article-title":"LAG-3: From Molecular Functions to Clinical Applications","volume":"8","author":"Maruhashi","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e18579","DOI":"10.1200\/JCO.2020.38.15_suppl.e18579","article-title":"Differential Immune Pathways in Classic and Mixed Variants of Anaplastic Thyroid Cancer","volume":"38","author":"Young","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18","DOI":"10.21037\/atm-21-4481","article-title":"Lymphocyte Activation Gene-3 Is Associated with Programmed Death-Ligand 1 and Programmed Cell Death Protein 1 in Small Cell Lung Cancer","volume":"9","author":"Sun","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.jtho.2017.01.019","article-title":"LAG-3 Protein Expression in Non\u2013Small Cell Lung Cancer and Its Relationship with PD-1\/PD-L1 and Tumor-Infiltrating Lymphocytes","volume":"12","author":"He","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.4049\/jimmunol.0800185","article-title":"LAG-3 Regulates Plasmacytoid Dendritic Cell Homeostasis","volume":"182","author":"Workman","year":"2009","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/imr.12520","article-title":"Tim-3 and Its Role in Regulating Anti-tumor Immunity","volume":"276","author":"Das","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1007\/s00262-023-03516-1","article-title":"TIM-3 as a Promising Target for Cancer Immunotherapy in a Wide Range of Tumors","volume":"72","author":"Sauer","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/ni1271","article-title":"The Tim-3 Ligand Galectin-9 Negatively Regulates T Helper Type 1 Immunity","volume":"6","author":"Zhu","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1002\/eji.200939274","article-title":"TIM-3 Is Expressed on Activated Human CD4+ T Cells and Regulates Th1 and Th17 Cytokines","volume":"39","author":"Hastings","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/j.ccell.2025.04.003","article-title":"Spatial and Multiomics Analysis of Human and Mouse Lung Adenocarcinoma Precursors Reveals TIM-3 as a Putative Target for Precancer Interception","volume":"43","author":"Zhu","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Gao, X., Zhu, Y., Li, G., Huang, H., Zhang, G., Wang, F., Sun, J., Yang, Q., Zhang, X., and Lu, B. (2012). TIM-3 Expression Characterizes Regulatory T Cells in Tumor Tissues and Is Associated with Lung Cancer Progression. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030676"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zang, K., Hui, L., Wang, M., Huang, Y., Zhu, X., and Yao, B. (2021). TIM-3 as a Prognostic Marker and a Potential Immunotherapy Target in Human Malignant Tumors: A Meta-Analysis and Bioinformatics Validation. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.579351"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15","DOI":"10.2147\/OTT.S4833","article-title":"CTLA-4 Blockade: Therapeutic Potential in Cancer Treatments","volume":"3","author":"Tarhini","year":"2010","journal-title":"OncoTargets Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"103482","DOI":"10.1016\/j.eclinm.2025.103482","article-title":"Impact of Platinum-Based Chemotherapy and CTLA-4 Inhibition on Acquired Resistance to First-Line Anti-PD-1\/PD-L1 Agents in Non-Small Cell Lung Cancer: A Systematic Review and Reconstructed Individual Patient Data Analysis","volume":"88","author":"Oresti","year":"2025","journal-title":"eClinicalMedicine"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Weiler, J., and Dittmar, T. (2019). Cell Fusion in Human Cancer: The Dark Matter Hypothesis. Cells, 8.","DOI":"10.3390\/cells8020132"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"106649","DOI":"10.1016\/j.biocel.2024.106649","article-title":"Cell-Cell Fusion in Cancer: The next Cancer Hallmark?","volume":"175","author":"Shultes","year":"2024","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eaat7828","DOI":"10.1126\/sciadv.aat7828","article-title":"Cell Fusion Potentiates Tumor Heterogeneity and Reveals Circulating Hybrid Cells That Correlate with Stage and Survival","volume":"4","author":"Gast","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1773204","DOI":"10.1080\/2162402X.2020.1773204","article-title":"Tumor Stem Cells Fuse with Monocytes to Form Highly Invasive Tumor-Hybrid Cells","volume":"9","author":"Aguirre","year":"2020","journal-title":"OncoImmunology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nrc2371","article-title":"Fusion of Tumour Cells with Bone Marrow-Derived Cells: A Unifying Explanation for Metastasis","volume":"8","author":"Pawelek","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Montalb\u00e1n-Hern\u00e1ndez, K., Cantero-Cid, R., Casalvilla-Due\u00f1as, J.C., Avenda\u00f1o-Ortiz, J., Mar\u00edn, E., Lozano-Rodr\u00edguez, R., Terr\u00f3n-Arcos, V., Vicario-Bravo, M., Marcano, C., and Saavedra-Ambrosy, J. (2022). Colorectal Cancer Stem Cells Fuse with Monocytes to Form Tumour Hybrid Cells with the Ability to Migrate and Evade the Immune System. Cancers, 14.","DOI":"10.3390\/cancers14143445"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s10238-024-01515-9","article-title":"Tumor-Immune Hybrid Cells Evade the Immune Response and Potentiate Colorectal Cancer Metastasis through CTLA4","volume":"25","author":"Tanjak","year":"2024","journal-title":"Clin. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41417-023-00693-0","article-title":"Cell Fusion Upregulates PD-L1 Expression for Evasion from Immunosurveillance","volume":"31","author":"Tajima","year":"2024","journal-title":"Cancer Gene Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13046-025-03337-3","article-title":"A Blood-Based Liquid Biopsy Analyzing Soluble Immune Checkpoints and Cytokines Identifies Distinct Neuroendocrine Tumors","volume":"44","author":"Celada","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12979-025-00535-7","article-title":"Age-Stratified Circulating Immune Signatures Reveal Non-Invasive Biomarkers for Colorectal Cancer Detection","volume":"22","author":"Cueto","year":"2025","journal-title":"Immun. 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