{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:59:23Z","timestamp":1790276363810,"version":"4.1.0"},"reference-count":111,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32571511"],"award-info":[{"award-number":["32571511"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["International Immunopharmacology"],"published-print":{"date-parts":[[2026,11]]},"DOI":"10.1016\/j.intimp.2026.117405","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:37:04Z","timestamp":1789666624000},"page":"117405","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Structural Foundation of CTLA-4 antibodies: Emerging Platforms for Next-generation Cancer Immunotherapy"],"prefix":"10.1016","volume":"189","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2953-5468","authenticated-orcid":false,"given":"Enat Mengistu","family":"Leta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suaad","family":"Syed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geleta Negasa","family":"Binegde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjin","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialong","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9403-4337","authenticated-orcid":false,"given":"Feng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"7","key":"10.1016\/j.intimp.2026.117405_b1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41573-021-00345-8","article-title":"The foundations of immune checkpoint blockade and the ipilimumab approval decennial","volume":"21","author":"Korman","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"issue":"11","key":"10.1016\/j.intimp.2026.117405_b2","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1038\/s41590-019-0512-0","article-title":"Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups","volume":"20","author":"Andrews","year":"2019","journal-title":"Nature Immunol."},{"key":"10.1016\/j.intimp.2026.117405_b3","first-page":"430","article-title":"Immune checkpoint proteins: a new therapeutic paradigm for cancer\u2014preclinical background: CTLA-4 and PD-1 blockade","volume":"vol. 37","author":"Weber","year":"2010"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41419-023-06389-5","article-title":"Mechanisms of immune checkpoint inhibitors: Insights into the regulation of circular RNAS involved in cancer hallmarks","volume":"15","author":"Meng","year":"2024","journal-title":"Cell Death & Dis."},{"issue":"4","key":"10.1016\/j.intimp.2026.117405_b5","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3390\/cells14040283","article-title":"Molecular mechanisms of immune regulation: A review","volume":"14","author":"Arneth","year":"2025","journal-title":"Cells"},{"issue":"4","key":"10.1016\/j.intimp.2026.117405_b6","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41568-022-00544-4","article-title":"Mechanisms driving the immunoregulatory function of cancer cells","volume":"23","author":"van Weverwijk","year":"2023","journal-title":"Nat. Rev. Cancer"},{"issue":"2","key":"10.1016\/j.intimp.2026.117405_b7","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1084\/jem.182.2.459","article-title":"CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation","volume":"182","author":"Krummel","year":"1995","journal-title":"J. Exp. Med."},{"issue":"5256","key":"10.1016\/j.intimp.2026.117405_b8","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1126\/science.271.5256.1734","article-title":"Enhancement of antitumor immunity by CTLA-4 blockade","volume":"271","author":"Leach","year":"1996","journal-title":"Science"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b9","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s13046-021-01987-7","article-title":"Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer","volume":"40","author":"Zhang","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3390\/ph15030335","article-title":"Revolutionization in cancer therapeutics via targeting major immune checkpoints PD-1, PD-L1 and CTLA-4","volume":"15","author":"Pandey","year":"2022","journal-title":"Pharmaceuticals"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41419-023-06391-x","article-title":"Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy","volume":"15","author":"Babamohamadi","year":"2024","journal-title":"Cell Death & Dis."},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b12","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1084\/jem.174.3.561","article-title":"CTLA-4 is a second receptor for the B cell activation antigen B7.","volume":"174","author":"Linsley","year":"1991","journal-title":"J. Exp. Med."},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b13","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.3390\/cancers13061440","article-title":"CTLA-4 in regulatory T cells for cancer immunotherapy","volume":"13","author":"Sobhani","year":"2021","journal-title":"Cancers"},{"issue":"23","key":"10.1016\/j.intimp.2026.117405_b14","doi-asserted-by":"crossref","first-page":"12848","DOI":"10.3390\/ijms252312848","article-title":"Tumor microenvironment drives the cross-talk between co-stimulatory and inhibitory molecules in tumor-infiltrating lymphocytes: implications for optimizing immunotherapy outcomes","volume":"25","author":"Franzese","year":"2024","journal-title":"Int. J. Mol. Sci."},{"issue":"31","key":"10.1016\/j.intimp.2026.117405_b15","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2300895120","article-title":"Both intratumoral regulatory T cell depletion and CTLA-4 antagonism are required for maximum efficacy of anti-CTLA-4 antibodies","volume":"120","author":"Lax","year":"2023","journal-title":"Proc. Natl. Acad. Sci."},{"key":"10.1016\/j.intimp.2026.117405_b16","article-title":"Overcoming resistance to PD-1 and CTLA-4 blockade mechanisms and therapeutic strategies","volume":"16","author":"Wang","year":"2025","journal-title":"Front. Immunol."},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b17","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.cell.2017.07.024","article-title":"Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade","volume":"170","author":"Wei","year":"2017","journal-title":"Cell"},{"key":"10.1016\/j.intimp.2026.117405_b18","article-title":"Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases","volume":"16","author":"Lu","year":"2025","journal-title":"Front. Immunol."},{"key":"10.1016\/j.intimp.2026.117405_b19","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1198365","article-title":"Current understanding of CTLA-4: from mechanism to autoimmune diseases","volume":"14","author":"Hossen","year":"2023","journal-title":"Front. Immunol."},{"issue":"12","key":"10.1016\/j.intimp.2026.117405_b20","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1038\/nm.3746","article-title":"Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations","volume":"20","author":"Schubert","year":"2014","journal-title":"Nature Med."},{"issue":"6204","key":"10.1016\/j.intimp.2026.117405_b21","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1126\/science.1255904","article-title":"Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4","volume":"345","author":"Kuehn","year":"2014","journal-title":"Science"},{"issue":"2","key":"10.1016\/j.intimp.2026.117405_b22","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1084\/jem.182.2.289","article-title":"Distinct roles for CD28 and cytotoxic T lymphocyte-associated molecule-4 receptors during T cell activation?","volume":"182","author":"Linsley","year":"1995","journal-title":"J. Exp. Med."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b23","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-pathol-042020-042741","article-title":"Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance","volume":"16","author":"Bagchi","year":"2021","journal-title":"Annu. Rev. Pathol.: Mech. Dis."},{"issue":"9","key":"10.1016\/j.intimp.2026.117405_b24","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental mechanisms of immune checkpoint blockade therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discov."},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b25","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.3390\/molecules24061190","article-title":"Molecular interactions of antibody drugs targeting PD-1, PD-L1, and CTLA-4 in immuno-oncology","volume":"24","author":"Lee","year":"2019","journal-title":"Molecules"},{"issue":"40","key":"10.1016\/j.intimp.2026.117405_b26","doi-asserted-by":"crossref","first-page":"67129","DOI":"10.18632\/oncotarget.18004","article-title":"Remarkably similar CTLA-4 binding properties of therapeutic ipilimumab and tremelimumab antibodies","volume":"8","author":"He","year":"2017","journal-title":"Oncotarget"},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b27","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3390\/ijtm5030028","article-title":"Protein engineering paving the way for next-generation therapies in cancer","volume":"5","author":"Naderiyan","year":"2025","journal-title":"Int. J. Transl. Med."},{"issue":"8","key":"10.1016\/j.intimp.2026.117405_b28","doi-asserted-by":"crossref","first-page":"4297","DOI":"10.1007\/s10238-023-01201-2","article-title":"Immune checkpoint targeting antibodies hold promise for combinatorial cancer therapeutics","volume":"23","author":"Ritu","year":"2023","journal-title":"Clin. Exp. Med."},{"issue":"21","key":"10.1016\/j.intimp.2026.117405_b29","doi-asserted-by":"crossref","first-page":"E4223","DOI":"10.1073\/pnas.1617941114","article-title":"Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab","volume":"114","author":"Ramagopal","year":"2017","journal-title":"Proc. Natl. Acad. Sci."},{"issue":"4","key":"10.1016\/j.intimp.2026.117405_b30","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.ccell.2018.02.010","article-title":"Fc effector function contributes to the activity of human anti-CTLA-4 antibodies","volume":"33","author":"Arce Vargas","year":"2018","journal-title":"Cancer Cell"},{"key":"10.1016\/j.intimp.2026.117405_b31","doi-asserted-by":"crossref","first-page":"563","DOI":"10.3389\/fimmu.2015.00563","article-title":"The timing of T cell priming and cycling","volume":"6","author":"Obst","year":"2015","journal-title":"Front. Immunol."},{"issue":"5","key":"10.1016\/j.intimp.2026.117405_b32","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.immuni.2016.04.020","article-title":"CD28 costimulation: from mechanism to therapy","volume":"44","author":"Esensten","year":"2016","journal-title":"Immunity"},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b33","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.immuni.2010.09.006","article-title":"Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation","volume":"33","author":"Yokosuka","year":"2010","journal-title":"Immunity"},{"key":"10.1016\/j.intimp.2026.117405_b34","article-title":"CTLA-4 and PD-1 combined blockade therapy for malignant melanoma brain metastases: mechanisms, challenges, and prospects","volume":"16","author":"Wang","year":"2025","journal-title":"Front. Immunol."},{"issue":"8","key":"10.1016\/j.intimp.2026.117405_b35","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1084\/jem.20082492","article-title":"Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti\u2013CTLA-4 antibodies","volume":"206","author":"Peggs","year":"2009","journal-title":"J. Exp. Med."},{"issue":"5899","key":"10.1016\/j.intimp.2026.117405_b36","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1126\/science.1160062","article-title":"CTLA-4 control over Foxp3+ regulatory T cell function","volume":"322","author":"Wing","year":"2008","journal-title":"Science"},{"key":"10.1016\/j.intimp.2026.117405_b37","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.3389\/fimmu.2018.02012","article-title":"Increased risk for malignancies in 131 affected CTLA4 mutation carriers","volume":"9","author":"Egg","year":"2018","journal-title":"Front. Immunol."},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b38","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.jaci.2018.02.055","article-title":"Phenotype, penetrance, and treatment of 133 CTLA-4-insufficient subjects","volume":"142","author":"Schwab","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b39","first-page":"58","article-title":"CTLA-4: a moving target in immunotherapy","volume":"131","author":"Rowshanravan","year":"2018","journal-title":"Blood, J. Am. Soc. Hematol."},{"issue":"7","key":"10.1016\/j.intimp.2026.117405_b40","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.3390\/ijms23073529","article-title":"Immune checkpoint receptors signaling in T cells","volume":"23","author":"Baldanzi","year":"2022","journal-title":"Int. J. Mol. Sci."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b41","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1146\/annurev.immunol.24.021605.090535","article-title":"A molecular perspective of CTLA-4 function","volume":"24","author":"Teft","year":"2006","journal-title":"Annu. Rev. Immunol."},{"issue":"6828","key":"10.1016\/j.intimp.2026.117405_b42","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/35069112","article-title":"Structural basis for co-stimulation by the human CTLA-4\/B7-2 complex","volume":"410","author":"Schwartz","year":"2001","journal-title":"Nature"},{"issue":"10","key":"10.1016\/j.intimp.2026.117405_b43","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.4049\/jimmunol.164.10.5319","article-title":"Structural analysis of CTLA-4 function in vivo","volume":"164","author":"Masteller","year":"2000","journal-title":"J. Immunol."},{"issue":"2","key":"10.1016\/j.intimp.2026.117405_b44","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/j.1476-5381.2009.00190.x","article-title":"Therapeutic antibodies: successes, limitations and hopes for the future","volume":"157","author":"Chames","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.intimp.2026.117405_b45","doi-asserted-by":"crossref","first-page":"619","DOI":"10.3389\/fimmu.2014.00619","article-title":"Diverse mechanisms regulate the surface expression of immunotherapeutic target ctla-4","volume":"5","author":"Schneider","year":"2014","journal-title":"Front. Immunol."},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b46","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.clim.2008.05.006","article-title":"Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis","volume":"128","author":"Gu","year":"2008","journal-title":"Clin. Immunol."},{"key":"10.1016\/j.intimp.2026.117405_b47","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.1033705","article-title":"In or out of control: Modulating regulatory T cell homeostasis and function with immune checkpoint pathways","volume":"13","author":"Abdeladhim","year":"2022","journal-title":"Front. Immunol."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b48","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s40164-025-00627-6","article-title":"Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy","volume":"14","author":"Hu","year":"2025","journal-title":"Exp. Hematol. Oncol."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b49","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S1074-7613(01)00259-X","article-title":"Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength","volume":"16","author":"Egen","year":"2002","journal-title":"Immunity"},{"issue":"11","key":"10.1016\/j.intimp.2026.117405_b50","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1002\/(SICI)1521-4141(199911)29:11<3596::AID-IMMU3596>3.0.CO;2-Y","article-title":"A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells","volume":"29","author":"Magistrelli","year":"1999","journal-title":"Eur. J. Immunol."},{"issue":"8","key":"10.1016\/j.intimp.2026.117405_b51","doi-asserted-by":"crossref","first-page":"513","DOI":"10.14348\/molcells.2022.2056","article-title":"Current understanding of cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling in T-cell biology and disease therapy","volume":"45","author":"Kim","year":"2022","journal-title":"Mol. Cells"},{"issue":"9","key":"10.1016\/j.intimp.2026.117405_b52","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2024.114768","article-title":"Rigid, bivalent CTLA-4 binding to CD80 is required to disrupt the cis CD80\/PD-L1 interaction","volume":"43","author":"Robinson","year":"2024","journal-title":"Cell Rep."},{"issue":"10","key":"10.1016\/j.intimp.2026.117405_b53","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2024.114834","article-title":"Context-restricted PD-(L) 1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity","volume":"43","author":"Oxley","year":"2024","journal-title":"Cell Rep."},{"issue":"7","key":"10.1016\/j.intimp.2026.117405_b54","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/nsb0797-527","article-title":"Solution structure of human CTLA-4 and delineation of a CD80\/CD86 binding site conserved in CD28","volume":"4","author":"Metzler","year":"1997","journal-title":"Nature Struct. Biol."},{"key":"10.1016\/j.intimp.2026.117405_b55","doi-asserted-by":"crossref","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."},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b56","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1084\/jem.185.3.393","article-title":"CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics","volume":"185","author":"van der Merwe","year":"1997","journal-title":"J. Exp. Med."},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b57","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1008825","article-title":"A computational study of co-inhibitory immune complex assembly at the interface between T cells and antigen presenting cells","volume":"17","author":"Su","year":"2021","journal-title":"PLoS Comput. Biol."},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b58","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.3390\/molecules29061330","article-title":"Mechanistic insights into the inhibition of a common CTLA-4 gene mutation in the cytoplasmic domain","volume":"29","author":"Xu","year":"2024","journal-title":"Molecules"},{"issue":"5","key":"10.1016\/j.intimp.2026.117405_b59","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S1074-7613(00)80346-5","article-title":"Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2","volume":"6","author":"Shiratori","year":"1997","journal-title":"Immunity"},{"key":"10.1016\/j.intimp.2026.117405_b60","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2022.728771","article-title":"CTLA-4 facilitates DNA damage\u2013induced apoptosis by interacting with PP2a","volume":"10","author":"Yan","year":"2022","journal-title":"Front. Cell Dev. Biology"},{"issue":"2","key":"10.1016\/j.intimp.2026.117405_b61","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.it.2014.12.001","article-title":"Confusing signals: recent progress in CTLA-4 biology","volume":"36","author":"Walker","year":"2015","journal-title":"Trends Immunol."},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b62","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S1074-7613(00)80480-X","article-title":"Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement","volume":"4","author":"Linsley","year":"1996","journal-title":"Immunity"},{"issue":"2","key":"10.1016\/j.intimp.2026.117405_b63","doi-asserted-by":"crossref","DOI":"10.1136\/esmoopen-2017-000213","article-title":"Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer","volume":"2","author":"Granier","year":"2017","journal-title":"ESMO Open"},{"issue":"8","key":"10.1016\/j.intimp.2026.117405_b64","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. Engl. J. Med."},{"issue":"6230","key":"10.1016\/j.intimp.2026.117405_b65","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1126\/science.aaa8172","article-title":"The future of immune checkpoint therapy","volume":"348","author":"Sharma","year":"2015","journal-title":"Science"},{"key":"10.1016\/j.intimp.2026.117405_b66","article-title":"Characterization of the high-affinity anti-CTLA-4 monoclonal antibody JS007 for immune checkpoint therapy of cancer","volume":"vol. 15","author":"Guan","year":"2023"},{"key":"10.1016\/j.intimp.2026.117405_b67","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.871802","article-title":"Impact of CTLA-4 checkpoint antibodies on ligand binding and transendocytosis","volume":"13","author":"Williams","year":"2022","journal-title":"Front. Immunol."},{"key":"10.1016\/j.intimp.2026.117405_b68","series-title":"Regulatory T-Cells: Methods and Protocols","first-page":"171","article-title":"In vitro analysis of CTLA-4-mediated transendocytosis by regulatory T cells","author":"Waters","year":"2022"},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b69","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/j.ccell.2018.05.005","article-title":"Selective Fc\u03b3R co-engagement on APCs modulates the activity of therapeutic antibodies targeting T cell antigens","volume":"33","author":"Waight","year":"2018","journal-title":"Cancer Cell"},{"key":"10.1016\/j.intimp.2026.117405_b70","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.625783","article-title":"The impact of Tregs on the anticancer immunity and the efficacy of immune checkpoint inhibitor therapies","volume":"12","author":"Gonz\u00e1lez-Navajas","year":"2021","journal-title":"Front. Immunol."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b71","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13578-018-0229-z","article-title":"Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of intratumoral regulatory T cells or checkpoint blockade?","volume":"8","author":"Tang","year":"2018","journal-title":"Cell & Biosci."},{"issue":"9","key":"10.1016\/j.intimp.2026.117405_b72","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1084\/jem.20130579","article-title":"Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti\u2013CTLA-4 therapy against melanoma","volume":"210","author":"Simpson","year":"2013","journal-title":"J. Exp. Med."},{"key":"10.1016\/j.intimp.2026.117405_b73","doi-asserted-by":"crossref","first-page":"9029","DOI":"10.1038\/s41467-025-64081-y","article-title":"A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice","volume":"16","author":"Cao","year":"2025","journal-title":"Nat. Commun."},{"issue":"8","key":"10.1016\/j.intimp.2026.117405_b74","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1039\/D4TB02083A","article-title":"Mechanistic understanding of pH as a driving force in cancer therapeutics","volume":"13","author":"Pandey","year":"2025","journal-title":"J. Mater. Chem. B"},{"issue":"4","key":"10.1016\/j.intimp.2026.117405_b75","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3390\/antib9040064","article-title":"Fc-engineering for modulated effector functions\u2014improving antibodies for cancer treatment","volume":"9","author":"Liu","year":"2020","journal-title":"Antibodies"},{"issue":"8","key":"10.1016\/j.intimp.2026.117405_b76","doi-asserted-by":"crossref","first-page":"6685","DOI":"10.1074\/jbc.M110.182394","article-title":"Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering","volume":"286","author":"Yu","year":"2011","journal-title":"J. Biol. Chem."},{"issue":"6828","key":"10.1016\/j.intimp.2026.117405_b77","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/35069118","article-title":"Crystal structure of the B7-1\/CTLA-4 complex that inhibits human immune responses","volume":"410","author":"Stamper","year":"2001","journal-title":"Nature"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b78","doi-asserted-by":"crossref","first-page":"13354","DOI":"10.1038\/ncomms13354","article-title":"Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy","volume":"7","author":"Lee","year":"2016","journal-title":"Nat. Commun."},{"key":"10.1016\/j.intimp.2026.117405_b79","article-title":"Engineered ipilimumab variants that bind human and mouse CTLA-4","volume":"vol. 17","author":"Robison","year":"2025"},{"key":"10.1016\/j.intimp.2026.117405_b80","article-title":"A functional antibody cross-reactive to both human and murine cytotoxic T-lymphocyte-associated protein 4 via binding to an N-glycosylation epitope","volume":"vol. 12","author":"Li","year":"2020"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b81","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s40164-024-00567-7","article-title":"Preclinical investigations and a first-in-human phase 1a trial of JS007, a novel anti-CTLA-4 antibody, in patients with advanced solid tumors","volume":"13","author":"Zhou","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"issue":"11","key":"10.1016\/j.intimp.2026.117405_b82","doi-asserted-by":"crossref","first-page":"5632","DOI":"10.3390\/ijms22115632","article-title":"Principles and current clinical landscape of multispecific antibodies against cancer","volume":"22","author":"Elshiaty","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.intimp.2026.117405_b83","article-title":"Improved therapeutic index of an acidic pH-selective antibody","volume":"vol. 14","author":"Lee","year":"2022"},{"issue":"4","key":"10.1016\/j.intimp.2026.117405_b84","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3390\/antib12040067","article-title":"Structure and dynamics guiding design of antibody therapeutics and vaccines","volume":"12","author":"Fern\u00e1ndez-Quintero","year":"2023","journal-title":"Antibodies"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b85","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/imr.13427","article-title":"Fc effector function of immune checkpoint blocking antibodies in oncology","volume":"328","author":"Martineau","year":"2024","journal-title":"Immunol. Rev."},{"key":"10.1016\/j.intimp.2026.117405_b86","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.3389\/fimmu.2018.03065","article-title":"Characterizing the diversity of the CDR-H3 loop conformational ensembles in relationship to antibody binding properties","volume":"9","author":"Fern\u00e1ndez-Quintero","year":"2019","journal-title":"Front. Immunol."},{"key":"10.1016\/j.intimp.2026.117405_b87","article-title":"Antibody-based cancer immunotherapy by targeting regulatory T cells","volume":"13","author":"Li","year":"2023","journal-title":"Front. Oncol."},{"issue":"23","key":"10.1016\/j.intimp.2026.117405_b88","doi-asserted-by":"crossref","first-page":"14179","DOI":"10.1080\/07391102.2023.2178509","article-title":"Computational analysis of structural and functional evaluation of the deleterious missense variants in the human CTLA4 gene","volume":"41","author":"Bouqdayr","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"issue":"2","key":"10.1016\/j.intimp.2026.117405_b89","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s11030-022-10452-2","article-title":"High-throughput virtual screening of small-molecule inhibitors targeting immune cell checkpoints to discover new immunotherapeutics for human diseases","volume":"27","author":"Singh","year":"2023","journal-title":"Mol. Divers."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b90","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s44342-024-00033-0","article-title":"Structural insights into antibody-based immunotherapy for hepatocellular carcinoma","volume":"23","author":"Shah","year":"2025","journal-title":"Genom. & Informatics"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b91","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s44276-023-00035-5","article-title":"Artificial intelligence-powered discovery of small molecules inhibiting CTLA-4 in cancer","volume":"2","author":"Sobhani","year":"2024","journal-title":"BJC Rep."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b92","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1021\/acs.nanolett.1c03584","article-title":"Mapping mechanostable pulling geometries of a therapeutic anticalin\/CTLA-4 protein complex","volume":"22","author":"Liu","year":"2021","journal-title":"Nano Lett."},{"issue":"9","key":"10.1016\/j.intimp.2026.117405_b93","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1111\/1759-7714.13541","article-title":"Meta-analysis of immune-related adverse events of immune checkpoint inhibitor therapy in cancer patients","volume":"11","author":"Song","year":"2020","journal-title":"Thorac. Cancer"},{"issue":"2","key":"10.1016\/j.intimp.2026.117405_b94","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1158\/1078-0432.CCR-23-2124","article-title":"FDA approval summary: tremelimumab in combination with durvalumab for the treatment of patients with unresectable hepatocellular carcinoma","volume":"30","author":"Patel","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"10.1016\/j.intimp.2026.117405_b95","article-title":"Impact of antibody fc engineering on translational pharmacology, and safety: insights from industry case studies","volume":"vol. 17","author":"Brennan","year":"2025"},{"issue":"6","key":"10.1016\/j.intimp.2026.117405_b96","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1038\/s41591-026-04323-8","article-title":"Gotistobart or docetaxel in metastatic squamous non-small cell lung cancer: stage 1 of the randomized phase 3 PRESERVE-003 trial","volume":"32","author":"Cho","year":"2026","journal-title":"Nature Med."},{"issue":"4","key":"10.1016\/j.intimp.2026.117405_b97","first-page":"567","article-title":"Fc-engineered anti-CTLA-4 antibody with enhanced ADCC activity eradicates tumors in cold tumor models by selective intratumoral Treg depletion","volume":"42","author":"Mimoto","year":"2024","journal-title":"Cancer Cell"},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b98","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41568-023-00637-8","article-title":"Fc\u03b3 receptors and immunomodulatory antibodies in cancer","volume":"24","author":"Galvez-Cancino","year":"2024","journal-title":"Nat. Rev. Cancer"},{"issue":"10","key":"10.1016\/j.intimp.2026.117405_b99","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/protein\/gzw040","article-title":"Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions","volume":"29","author":"Schlothauer","year":"2016","journal-title":"Protein Eng. Des. Sel."},{"issue":"12","key":"10.1016\/j.intimp.2026.117405_b100","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2023-007785","article-title":"XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer","volume":"11","author":"Jenkins","year":"2023","journal-title":"J. Immunother. Cancer"},{"issue":"Suppl 16","key":"10.1016\/j.intimp.2026.117405_b101","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1200\/JCO.2025.43.16_suppl.3553","article-title":"Vilastobart (XTX101), a tumor-activated, Fc-enhanced anti\u2013CTLA-4 monoclonal antibody, in combination with atezolizumab in patients with MSS CRC","volume":"43","author":"Fakih","year":"2025","journal-title":"J. Clin. Oncol."},{"issue":"5","key":"10.1016\/j.intimp.2026.117405_b102","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1158\/2159-8290.CD-20-1445","article-title":"Design and efficacy of a monovalent bispecific PD-1\/CTLA4 antibody that enhances CTLA4 blockade on PD-1+ activated T cells","volume":"11","author":"Dovedi","year":"2021","journal-title":"Cancer Discov."},{"issue":"12_Supplement","key":"10.1016\/j.intimp.2026.117405_b103","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2022-CT016","article-title":"Abstract CT016: MEDI5752, a novel PD-1\/CTLA-4 bispecific checkpoint inhibitor for advanced solid tumors: First-in-human study","volume":"82","author":"Tran","year":"2022","journal-title":"Cancer Res."},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b104","article-title":"KN046, a bispecific antibody against PD-L1 and CTLA-4, plus chemotherapy as first-line treatment for metastatic NSCLC: A multicenter phase 2 trial","volume":"5","author":"Zhao","year":"2024","journal-title":"Cell Rep. Med."},{"key":"10.1016\/j.intimp.2026.117405_b105","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2024.111998","article-title":"Identification of TAP1 as a T-cell related therapeutic target in gastric cancer by mediating oxalipliatin-related synergistic enhancement of immunotherapy","volume":"132","author":"Zhao","year":"2024","journal-title":"Int. Immunopharmacol."},{"issue":"1","key":"10.1016\/j.intimp.2026.117405_b106","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1146\/annurev-pharmtox-010818-021118","article-title":"Engineered protein scaffolds as next-generation therapeutics","volume":"60","author":"Gebauer","year":"2020","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"10.1016\/j.intimp.2026.117405_b107","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2025.1498697","article-title":"Trifunctional antibody-cytokine fusion protein formats for tumor-targeted combination of IL-15 with IL-7 or IL-21","volume":"16","author":"M\u00f6ller","year":"2025","journal-title":"Front. Immunol."},{"issue":"7873","key":"10.1016\/j.intimp.2026.117405_b108","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"10.1016\/j.intimp.2026.117405_b109","doi-asserted-by":"crossref","DOI":"10.3389\/fmolb.2025.1688455","article-title":"High-resolution protein modeling through Cryo-EM and AI: current trends and future perspectives\u2013a review","volume":"12","author":"Jeyaraj","year":"2025","journal-title":"Front. Mol. Biosci."},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b110","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1097\/CAD.0000000000001565","article-title":"Tumor neoantigens derived from RNA editing events show significant clinical relevance in melanoma patients treated with immunotherapy","volume":"35","author":"Lu","year":"2024","journal-title":"Anticancer Drugs"},{"issue":"3","key":"10.1016\/j.intimp.2026.117405_b111","doi-asserted-by":"crossref","first-page":"S154","DOI":"10.1016\/j.jtho.2021.01.179","article-title":"MA06. 09 preliminary safety, efficacy results of KN046 (bispecific anti-PD-L1\/CTLA4) in subjects with rare thoracic tumors","volume":"16","author":"Richardson","year":"2021","journal-title":"J. Thorac. Oncol."}],"container-title":["International Immunopharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S156757692601252X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S156757692601252X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:05:41Z","timestamp":1790273141000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S156757692601252X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,11]]},"references-count":111,"alternative-id":["S156757692601252X"],"URL":"https:\/\/doi.org\/10.1016\/j.intimp.2026.117405","relation":{},"ISSN":["1567-5769"],"issn-type":[{"value":"1567-5769","type":"print"}],"subject":[],"published":{"date-parts":[[2026,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Structural Foundation of CTLA-4 antibodies: Emerging Platforms for Next-generation Cancer Immunotherapy","name":"articletitle","label":"Article Title"},{"value":"International Immunopharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.intimp.2026.117405","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"117405"}}