{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:45:11Z","timestamp":1790959511123,"version":"4.1.0"},"reference-count":124,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Science and Technology Council of Taiwan","award":["114-2314-B-002-067-MY3"],"award-info":[{"award-number":["114-2314-B-002-067-MY3"]}]},{"name":"the National Science and Technology Council of Taiwan","award":["114-3111-Y-042-001"],"award-info":[{"award-number":["114-3111-Y-042-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>B and T lymphocyte attenuator (BTLA) is a unique co-inhibitory receptor of the CD28 immunoglobulin superfamily that exhibits dual regulatory functions in immune activation and tolerance. Unlike PD-1 or CTLA-4, BTLA interacts bidirectionally with its ligand HVEM, forming a complex signaling network that shapes immune homeostasis within the tumor microenvironment. Dysregulated BTLA expression has been associated with tumor immune evasion and poor prognosis in several cancers. Owing to its distinctive molecular features and multifaceted immunoregulatory roles, BTLA represents an emerging therapeutic target, particularly in tumors unresponsive to conventional immune checkpoint inhibitors. This review provides a comprehensive overview of BTLA\u2019s structure, signaling mechanisms, and functional implications in tumor immunity and discusses current advances and challenges in BTLA-targeted therapy. Finally, we outline future perspectives on leveraging BTLA modulation to enhance cancer immunotherapy outcomes.<\/jats:p>","DOI":"10.3390\/ph18121784","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T11:47:22Z","timestamp":1763984842000},"page":"1784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["BTLA: An Emerging Immune Checkpoint Target in Cancer Immunotherapy"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8377-1796","authenticated-orcid":false,"given":"Ming-Cheng","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Isotope Application Research, National Atomic Research Institute, No. 1000, Wenhua Rd., Longtan Dist., Taoyuan City 325207, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Chi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Isotope Application Research, National Atomic Research Institute, No. 1000, Wenhua Rd., Longtan Dist., Taoyuan City 325207, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jou","family":"Tai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 100226, Taiwan"},{"name":"Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100226, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8958-5222","authenticated-orcid":false,"given":"Ying-Cheng","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 100226, Taiwan"},{"name":"Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100226, Taiwan"},{"name":"Department of Obstetrics and Gynecology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City 300195, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102333","DOI":"10.1016\/j.jaut.2019.102333","article-title":"Immune checkpoint molecules. Possible future therapeutic implications in autoimmune diseases","volume":"104","author":"Huang","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mejia-Guarnizo, L.V., Monroy-Camacho, P.S., Turizo-Smith, A.D., and Rodriguez-Garcia, J.A. (2023). The role of immune checkpoints in antitumor response: A potential antitumor immunotherapy. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1298571"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/bjc.2017.434","article-title":"Mechanisms of resistance to immune checkpoint inhibitors","volume":"118","author":"Jenkins","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12943-023-01845-4","article-title":"Beyond the anti-PD-1\/PD-L1 era: Promising role of the BTLA\/HVEM axis as a future target for cancer immunotherapy","volume":"22","author":"Rodrigo","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4561571","DOI":"10.1155\/2018\/4561571","article-title":"Distinct Changes of BTLA and HVEM Expressions in Circulating CD4+ and CD8+ T Cells in Hepatocellular Carcinoma Patients","volume":"2018","author":"Liu","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/ni944","article-title":"BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1","volume":"4","author":"Watanabe","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Parvez, A., Choudhary, F., Mudgal, P., Khan, R., Qureshi, K.A., Farooqi, H., and Aspatwar, A. (2023). PD-1 and PD-L1: Architects of immune symphony and immunotherapy breakthroughs in cancer treatment. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1296341"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"450","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":"ref_9","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.3390\/curroncol29050247","article-title":"Immune Checkpoint Inhibitors in Cancer Therapy","volume":"29","author":"Shiravand","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Girigoswami, A., and Girigoswami, K. (2023). Potential Applications of Nanoparticles in Improving the Outcome of Lung Cancer Treatment. Genes, 14.","DOI":"10.3390\/genes14071370"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1182\/blood-2017-06-741033","article-title":"CTLA-4: A moving target in immunotherapy","volume":"131","author":"Rowshanravan","year":"2018","journal-title":"Blood"},{"key":"ref_12","first-page":"412","article-title":"Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma","volume":"166","author":"Quirk","year":"2015","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.immuni.2024.01.010","article-title":"LAG-3, TIM-3, and TIGIT: Distinct functions in immune regulation","volume":"57","author":"Joller","year":"2024","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"104532","DOI":"10.1016\/j.cellimm.2022.104532","article-title":"The role of the BTLA-HVEM complex in the pathogenesis of autoimmune diseases","volume":"376","author":"Wojciechowicz","year":"2022","journal-title":"Cell. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Deng, Z., Zheng, Y., Cai, P., and Zheng, Z. (2021). The Role of B and T Lymphocyte Attenuator in Respiratory System Diseases. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.635623"},{"key":"ref_16","first-page":"10224","article-title":"Differences in Co-Expression of T Cell Co-Inhibitory and Co-Stimulatory Molecules with PD-1 Across Different Human Cancers","volume":"9","author":"Tarhini","year":"2024","journal-title":"J. Oncol. Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Andrzejczak, A., and Karabon, L. (2024). BTLA biology in cancer: From bench discoveries to clinical potentials. Biomark. Res., 12.","DOI":"10.1186\/s40364-024-00556-2"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1158\/0008-5472.CAN-11-2637","article-title":"CD8+ T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1","volume":"72","author":"Fourcade","year":"2012","journal-title":"Cancer Res."},{"key":"ref_19","first-page":"223","article-title":"HVEM\/LIGHT\/BTLA\/CD160 cosignaling pathways as targets for immune regulation","volume":"87","author":"Lucas","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1600-065X.2009.00783.x","article-title":"The CD160, BTLA, LIGHT\/HVEM pathway: A bidirectional switch regulating T-cell activation","volume":"229","author":"Cai","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.immuni.2016.10.008","article-title":"Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells","volume":"45","author":"Jones","year":"2016","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"110253","DOI":"10.1016\/j.isci.2024.110253","article-title":"BTLA and PD-1 signals attenuate TCR-mediated transcriptomic changes","volume":"27","author":"Arifin","year":"2024","journal-title":"iScience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/eji.201948456","article-title":"The immune checkpoint receptor associated phosphatases SHP-1 and SHP-2 are not required for gammadeltaT17 cell development, activation, or skin inflammation","volume":"50","author":"Kadekar","year":"2020","journal-title":"Eur. J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Xu, X., Hou, B., Fulzele, A., Masubuchi, T., Zhao, Y., Wu, Z., Hu, Y., Jiang, Y., Ma, Y., and Wang, H. (2020). PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2. J. Cell Biol., 219.","DOI":"10.1083\/jcb.201905085"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-025-02280-1","article-title":"Immune evasion in cancer: Mechanisms and cutting-edge therapeutic approaches","volume":"10","author":"Tufail","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yu, L., Sun, M., Zhang, Q., Zhou, Q., and Wang, Y. (2022). Harnessing the immune system by targeting immune checkpoints: Providing new hope for Oncotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.982026"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ning, Z., Liu, K., and Xiong, H. (2021). Roles of BTLA in Immunity and Immune Disorders. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.654960"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101794","DOI":"10.1016\/j.tranon.2023.101794","article-title":"Charting new frontiers: Co-inhibitory immune checkpoint proteins in therapeutics, biomarkers, and drug delivery systems in cancer care","volume":"38","author":"Xiao","year":"2023","journal-title":"Transl. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yu, X., Zheng, Y., Mao, R., Su, Z., and Zhang, J. (2019). BTLA\/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00617"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"156412","DOI":"10.1016\/j.cyto.2023.156412","article-title":"BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression","volume":"172","author":"Mohamed","year":"2023","journal-title":"Cytokine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2147\/OTT.S232234","article-title":"BTLA Expression in Stage I-III Non-Small-Cell Lung Cancer and Its Correlation with PD-1\/PD-L1 and Clinical Outcomes","volume":"13","author":"Li","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116231","DOI":"10.1016\/j.ejmech.2024.116231","article-title":"The BTLA-HVEM complex\u2014The future of cancer immunotherapy","volume":"268","author":"Wojciechowicz","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Drewniak-Switalska, M., Fortuna, P., and Krzystek-Korpacka, M. (2025). Negative Immune Checkpoint Inhibitors. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17060713"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.str.2019.05.010","article-title":"Structural Basis of CD160:HVEM Recognition","volume":"27","author":"Liu","year":"2019","journal-title":"Structure"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Patsoukis, N., Duke-Cohan, J.S., Chaudhri, A., Aksoylar, H.I., Wang, Q., Council, A., Berg, A., Freeman, G.J., and Boussiotis, V.A. (2020). Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Commun. Biol., 3.","DOI":"10.1038\/s42003-020-0845-0"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1016\/j.bbrc.2003.11.070","article-title":"Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2","volume":"312","author":"Gavrieli","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e74276","DOI":"10.7554\/eLife.74276","article-title":"Molecular features underlying differential SHP1\/SHP2 binding of immune checkpoint receptors","volume":"10","author":"Xu","year":"2021","journal-title":"eLife"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bourque, J., and Hawiger, D. (2019). The BTLA-HVEM-CD5 Immunoregulatory Axis-An Instructive Mechanism Governing pTreg Cell Differentiation. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01163"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1002304","DOI":"10.37349\/etat.2025.1002304","article-title":"Key immune cells and their crosstalk in the tumor microenvironment of bladder cancer: Insights for innovative therapies","volume":"6","author":"Balkhi","year":"2025","journal-title":"Explor. Target. Anti-Tumor Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"He, Y., Vlaming, M., van Meerten, T., and Bremer, E. (2022). The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity. Cancers, 14.","DOI":"10.3390\/cancers14020299"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.coi.2011.08.008","article-title":"TNF Superfamily Networks: Bidirectional and interference pathways of the herpesvirus entry mediator (TNFSF14)","volume":"23","author":"Ware","year":"2011","journal-title":"Curr. Opin. Immunol."},{"key":"ref_42","first-page":"266","article-title":"Focusing on CD8+ T-cell phenotypes: Improving solid tumor therapy","volume":"43","author":"Yao","year":"2024","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.bj.2022.03.008","article-title":"Negative times negative equals positive, THEMIS sets the rule on thymic selection and peripheral T cell responses","volume":"45","author":"Melique","year":"2022","journal-title":"Biomed. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"735","DOI":"10.4161\/onci.20823","article-title":"PD-1 and BTLA and CD8+ T-cell \u201cexhaustion\u201d in cancer: \u201cExercising\u201d an alternative viewpoint","volume":"1","author":"Haymaker","year":"2012","journal-title":"Oncoimmunology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.imbio.2009.09.008","article-title":"Detection of protein on BTLAlow cells and in vivo antibody-mediated down-modulation of BTLA on lymphoid and myeloid cells of C57BL\/6 and BALB\/c BTLA allelic variants","volume":"215","author":"Kaye","year":"2010","journal-title":"Immunobiology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sordo-Bahamonde, C., Lorenzo-Herrero, S., Gonzalez-Rodriguez, A.P., Payer, \u00c1.R., Gonz\u00e1lez-Garc\u00eda, E., L\u00f3pez-Soto, A., and Gonzalez, S. (2021). BTLA\/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia. Cancers, 13.","DOI":"10.3390\/cancers13081766"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Neophytou, C.M., Panagi, M., Stylianopoulos, T., and Papageorgis, P. (2021). The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities. Cancers, 13.","DOI":"10.3390\/cancers13092053"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Yang, Y., Zeng, Y., Qu, Q., Shen, D., Mu, C., Lei, W., Su, M., Mao, J., and Gao, L. (2025). B and T lymphocyte attenuator (BTLA) and PD-1 pathway dual blockade promotes antitumor immune responses by reversing CD8+ T-cell exhaustion in non-small cell lung cancer. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1553042"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e1200778","DOI":"10.1080\/2162402X.2016.1200778","article-title":"Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk","volume":"5","author":"Li","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e1254855","DOI":"10.1080\/2162402X.2016.1254855","article-title":"BTLA identifies dysfunctional PD-1-expressing CD4+ T cells in human hepatocellular carcinoma","volume":"5","author":"Zhao","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1158\/1078-0432.CCR-16-1217","article-title":"Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter","volume":"23","author":"Ritthipichai","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Song, J., and Wu, L. (2020). Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer. Front. Mol. Biosci., 7.","DOI":"10.3389\/fmolb.2020.00148"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.exphem.2018.01.003","article-title":"BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints","volume":"60","author":"Quan","year":"2018","journal-title":"Exp. Hematol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1186\/s40425-019-0744-4","article-title":"BTLA blockade enhances Cancer therapy by inhibiting IL-6\/IL-10-induced CD19(high) B lymphocytes","volume":"7","author":"Chen","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Fanale, D., Brando, C., Corsini, L.R., Cutaia, S., Di Donna, M.C., Randazzo, U., Filorizzo, C., Lisanti, C., Magrin, L., and Gurrera, V. (2023). Low plasma PD-L1 levels, early tumor onset and absence of peritoneal carcinomatosis improve prognosis of women with advanced high-grade serous ovarian cancer. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10911-5"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e42030","DOI":"10.1097\/MD.0000000000042030","article-title":"Development and evaluation of an ovarian cancer prognostic model based on adaptive immune-related genes","volume":"104","author":"Shi","year":"2025","journal-title":"Medicine"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4917","DOI":"10.1158\/1078-0432.CCR-12-1972","article-title":"Molecular pathways: Coexpression of immune checkpoint molecules: Signaling pathways and implications for cancer immunotherapy","volume":"19","author":"Nirschl","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1158\/1078-0432.CCR-25-0022","article-title":"Phase I\/II Study of Tifcemalimab, an Anti-B- and T-lymphocyte Attenuator Antibody, in Combination with Toripalimab in Previously Treated Advanced Lung Cancer","volume":"31","author":"Cheng","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Liu, F., Chen, H., Wu, S., Zhu, C., Zhang, M., Rui, W., Zhou, D., Wang, Y., Lin, X., and Zhao, X. (2025). Neoepitope BTLAP267L-specific TCR-T cell immunotherapy unlocks precision treatment for hepatocellular carcinoma. Cancer Biol. Med., 22.","DOI":"10.20892\/j.issn.2095-3941.2024.0434"},{"key":"ref_61","first-page":"10732748241270583","article-title":"Development of a Novel CD8+ T Cell-Associated Signature for Prognostic Assessment in Hepatocellular Carcinoma","volume":"31","author":"Li","year":"2024","journal-title":"Cancer Control J. Moffitt Cancer Cent."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e1014246","DOI":"10.1080\/2162402X.2015.1014246","article-title":"BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties","volume":"4","author":"Haymaker","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1172\/JCI40070","article-title":"BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination","volume":"120","author":"Derre","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Dong, X., Song, J., Chen, B., Qi, Y., Jiang, W., Li, H., Zheng, D., Wang, Y., Zhang, X., and Liu, H. (2020). Exploration of the Prognostic and Immunotherapeutic Value of B and T Lymphocyte Attenuator in Skin Cutaneous Melanoma. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.592811"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Mihaila, R.I., Gheorghe, A.S., Zob, D.L., and Stanculeanu, D.L. (2024). The Importance of Predictive Biomarkers and Their Correlation with the Response to Immunotherapy in Solid Tumors-Impact on Clinical Practice. Biomedicines, 12.","DOI":"10.3390\/biomedicines12092146"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Willsmore, Z.N., Harris, R.J., Crescioli, S., Hussein, K., Kakkassery, H., Thapa, D., Cheung, A., Chauhan, J., Bax, H.J., and Chenoweth, A. (2020). B Cells in Patients with Melanoma: Implications for Treatment with Checkpoint Inhibitor Antibodies. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.622442"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"101851","DOI":"10.1016\/j.tranon.2023.101851","article-title":"Anti-PD-1\/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations","volume":"40","author":"Chen","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e1008858","DOI":"10.1080\/2162402X.2015.1008858","article-title":"Immune checkpoint blockade in microsatellite instable colorectal cancers: Back to the clinic","volume":"4","author":"Housseau","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Takahara, T., Nakamura, S., Tsuzuki, T., and Satou, A. (2023). The Immunology of DLBCL. Cancers, 15.","DOI":"10.3390\/cancers15030835"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"a001719","DOI":"10.1101\/mcs.a001719","article-title":"Diffuse large B-cell lymphoma: Can genomics improve treatment options for a curable cancer?","volume":"3","author":"Amin","year":"2017","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1007\/s00262-023-03435-1","article-title":"BTLA dysregulation correlates with poor outcome and diminished T cell-mediated antitumor responses in chronic lymphocytic leukemia","volume":"72","author":"Payer","year":"2023","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhang, J.-A., Lu, Y.-B., Wang, W.-D., Liu, G.-B., Chen, C., Shen, L., Luo, H.-L., Xu, H., Peng, Y., and Luo, H. (2020). BTLA-Expressing Dendritic Cells in Patients with Tuberculosis Exhibit Reduced Production of IL-12\/IFN-\u03b1 and Increased Production of IL-4 and TGF-\u03b2, Favoring Th2 and Foxp3+ Treg Polarization. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00518"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Li, S., Liu, J., Wu, J., and Zheng, X. (2025). Immunological Mechanisms and Effects of Bacterial Infections in Acute-on-Chronic Liver Failure. Cells, 14.","DOI":"10.3390\/cells14100718"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"110553","DOI":"10.1016\/j.celrep.2022.110553","article-title":"Btla signaling in conventional and regulatory lymphocytes coordinately tempers humoral immunity in the intestinal mucosa","volume":"38","author":"Stienne","year":"2022","journal-title":"Cell Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1956142","DOI":"10.1080\/2162402X.2021.1956142","article-title":"Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma","volume":"10","author":"Choi","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Tojjari, A., Saeed, A., Sadeghipour, A., Kurzrock, R., and Cavalcante, L. (2023). Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches. Cancers, 15.","DOI":"10.3390\/cancers15225384"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1038\/s41467-024-46047-8","article-title":"BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion","volume":"15","author":"Yu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Aubergeon, L., Sawaf, M., Felten, R., Gottenberg, J.E., Dumortier, H., and Monneaux, F. (2021). High BTLA Expression Likely Contributes to Contraction of the Regulatory T Cell Subset in Lupus Disease. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.767099"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5036","DOI":"10.4049\/jimmunol.1501973","article-title":"Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent to Oral Intervention in Experimental Autoimmune Encephalomyelitis","volume":"196","author":"Huarte","year":"2016","journal-title":"J. Immunol."},{"key":"ref_80","first-page":"62","article-title":"Blockade of novel immune checkpoints and new therapeutic combinations to boost antitumor immunity","volume":"41","author":"Domuro","year":"2022","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1146\/annurev-immunol-030409-101202","article-title":"Slow down and survive: Enigmatic immunoregulation by BTLA and HVEM","volume":"28","author":"Murphy","year":"2010","journal-title":"Annu. Rev. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e009841","DOI":"10.1136\/jitc-2024-009841","article-title":"BTLA promoter hypomethylation correlates with enhanced immune cell infiltration, favorable prognosis, and immunotherapy response in melanoma","volume":"13","author":"Yang","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1039\/D4BM01732C","article-title":"Overcoming the novel glycan-lectin checkpoints in tumor microenvironments for the success of the cross-presentation-based immunotherapy","volume":"13","author":"Jain","year":"2025","journal-title":"Biomater. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e2500304","DOI":"10.1200\/PO-25-00304","article-title":"Pan-Cancer Landscape of B- and T-Lymphocyte Attenuator: Implications for Potential Immunotherapy Combinations","volume":"9","author":"Nishizaki","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1080\/10428194.2018.1564827","article-title":"Divergent LAG-3 versus BTLA, TIGIT, and FCRL3 expression in Sezary syndrome","volume":"60","author":"Anzengruber","year":"2019","journal-title":"Leuk. Lymphoma"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/s41590-024-01847-4","article-title":"The BTLA-HVEM axis restricts CAR T cell efficacy in cancer","volume":"25","author":"Guruprasad","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Tang, P., Shen, X., Gao, J., Zhang, J., Feng, Y., Zhang, J., Huang, Z., and Wang, X. (2024). Distinct characteristics of BTLA\/HVEM axis expression on Tregs and its impact on the expansion and attributes of Tregs in patients with active pulmonary tuberculosis. Front. Cell. Infect. Microbiol., 14.","DOI":"10.3389\/fcimb.2024.1437207"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"919","DOI":"10.2147\/OTT.S128825","article-title":"Increased BTLA and HVEM in gastric cancer are associated with progression and poor prognosis","volume":"10","author":"Lan","year":"2017","journal-title":"OncoTargets Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"S1645","DOI":"10.1016\/j.annonc.2024.10.677","article-title":"644P Tifcemalimab combined with toripalimab and docetaxel as 2nd line treatment for immunotherapy-treated squamous cell non-small cell lung cancer (Sq-NSCLC) patients: A phase Ib\/II study","volume":"35","author":"Lv","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Ding, C., Zhang, Y., Xia, T., Li, J., Yao, W., Zhang, Q., Han, Z., Wang, J., Cao, Z., and Hu, J. (2025). Perioperative the BTLA inhibitor (tifcemalimab) combined with toripalimab and chemotherapy for resectable locally advanced thoracic esophageal squamous cell carcinoma trial (BT-NICE trial): A prospective, single-arm, exploratory study. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1542877"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4559","DOI":"10.1038\/s41467-025-59461-3","article-title":"Tifcemalimab as monotherapy or in combination with toripalimab in patients with relapsed\/refractory lymphoma: A Phase I trial","volume":"16","author":"Song","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"AB17","DOI":"10.1016\/j.jaad.2024.07.078","article-title":"50585 ANB032, a B and T Cell Lymphocyte Attenuator (BTLA) Checkpoint Receptor Agonist, Modulates Dendritic Cell (DC) Maturation and Function: A Novel Mechanism Addressing Atopic Dermatitis Pathophysiology","volume":"91","author":"Muench","year":"2024","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_93","unstructured":"Lewis, D., Winner, P., Saper, J., Ness, S., Polverejan, E., Wang, S., Kurland, C.L., Nye, J., Yuen, E., and Eerdekens, M. (2023, January 15\u201318). Phase 2, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of ANB032 in the Treatment of Subjects with Moderate to Severe Atopic Dermatitis. Proceedings of the 5th Inflammatory Skin Disease Summit, Vienna, Austria."},{"key":"ref_94","unstructured":"(2025, November 01). A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Two-Arm, Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of LY3361237 as a Treatment for Adults with At Least Moderately Active Systemic Lupus Erythematosus, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05123586."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"S684","DOI":"10.1016\/j.annonc.2024.08.1065","article-title":"1006P Phase I dose escalation study of HFB200603, a best-in-class BTLA antagonist monoclonal antibody (mAb), in monotherapy and in combination with the anti-PD-1 mAb tislelizumab (TIS) in adult patients (pts) with advanced solid tumors","volume":"35","author":"Gambardella","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_96","unstructured":"(2025, November 01). A Phase 1a\/1b, Open-Label, Multi-Center, Dose Escalation and Expansion Study of HFB200603 (Anti-BTLA Antibody) as a Single Agent and in Combination with Tislelizumab (Anti-PD-1 Antibody) in Adult Patients with Advanced Solid Tumors, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05789069."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Battin, C., Leitner, J., Waidhofer-Sollner, P., Grabmeier-Pfistershammer, K., Olive, D., and Steinberger, P. (2022). BTLA inhibition has a dominant role in the cis-complex of BTLA and HVEM. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.956694"},{"key":"ref_98","unstructured":"(2025, November 01). A Randomized, Double-Blind, Placebo-Controlled, Multi-Regional Phase III Clinical Study of Toripalimab Alone or in Combination with Tifcemalimab (JS004\/TAB004) as Consolidation Therapy in Patients with Limited-Stage Small Cell Lung Cancer Without Disease Progression Following Chemoradiotherapy, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06095583."},{"key":"ref_99","unstructured":"(2025, November 01). A Phase Ib\/II Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Initial Efficacy of Recombinant Humanized Anti-BTLA Monoclonal Antibody (JS004) Injection Combined with Toripalimab and with Standard Chemotherapy in Patients with Advanced Lung Cancer, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05664971."},{"key":"ref_100","unstructured":"(2025, November 01). Toripalimab and JS004 Combined with Platinum-Based Chemotherapy for Relapsed and Extensive-Stage Small Cell Lung Cancer: A Single-Center, Randomized Trial, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06648200."},{"key":"ref_101","unstructured":"(2025, November 01). Exploratory Clinical Study of Low-Dose Radiotherapy Combined with Concurrent Chemotherapy, Toripalimab and Tifcemalimab in First-Line Treatment of Extensive-Stage Small Cell Lung Cancer, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06732258."},{"key":"ref_102","unstructured":"(2025, November 01). A Single Center, Prospective, Randomized Controlled, Second-Line Clinical Study on the Combination of Toripalimab and JS004 in the Treatment for Recurrent and Metastatic Clear Cell Renal Cell Carcinoma, Available online: https:\/\/www.clinicaltrials.gov\/study\/NCT06690697."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.4110\/in.2020.20.e9","article-title":"Clinical Characteristics and Treatment of Immune-Related Adverse Events of Immune Checkpoint Inhibitors","volume":"20","author":"Choi","year":"2020","journal-title":"Immune Netw."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Yasmeen, F., Pirzada, R.H., Ahmad, B., Choi, B., and Choi, S. (2024). Understanding Autoimmunity: Mechanisms, Predisposing Factors, and Cytokine Therapies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147666"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"57","DOI":"10.5483\/BMBRep.2022.55.2.183","article-title":"Emerging role of bystander T cell activation in autoimmune diseases","volume":"55","author":"Shim","year":"2022","journal-title":"BMB Rep."},{"key":"ref_106","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_107","doi-asserted-by":"crossref","first-page":"100880","DOI":"10.1016\/j.jhepr.2023.100880","article-title":"Burden of grade 3 or 4 liver injury associated with immune checkpoint inhibitors","volume":"5","author":"Parlati","year":"2023","journal-title":"JHEP Rep. Innov. Hepatol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.coi.2013.04.001","article-title":"Phosphatase regulation of immunoreceptor signaling in T cells, B cells and mast cells","volume":"25","author":"Bounab","year":"2013","journal-title":"Curr. Opin. Immunol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Baldanzi, G. (2022). Immune Checkpoint Receptors Signaling in T Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073529"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1093\/cei\/uxac029","article-title":"Mechanisms of induction of regulatory B cells in the tumour microenvironment and their contribution to immunosuppression and pro-tumour responses","volume":"209","author":"Blair","year":"2022","journal-title":"Clin. Exp. Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Catalan, D., Mansilla, M.A., Ferrier, A., Soto, L., Oleinika, K., Aguillon, J.C., and Aravena, O. (2021). Immunosuppressive Mechanisms of Regulatory B Cells. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.611795"},{"key":"ref_112","first-page":"e2056","article-title":"B cell responses and antibody-based therapeutic perspectives in human cancers","volume":"7","author":"Mandal","year":"2024","journal-title":"Cancer Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"6248590","DOI":"10.1155\/2018\/6248590","article-title":"Altered NKp30, NKp46, NKG2D, and DNAM-1 Expression on Circulating NK Cells Is Associated with Tumor Progression in Human Gastric Cancer","volume":"2018","author":"Han","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Alspach, E., Lussier, D.M., and Schreiber, R.D. (2019). Interferon gamma and Its Important Roles in Promoting and Inhibiting Spontaneous and Therapeutic Cancer Immunity. Cold Spring Harb. Perspect. Biol., 11.","DOI":"10.1101\/cshperspect.a028480"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.molimm.2021.03.007","article-title":"Up-regulation of BTLA expression in myeloid dendritic cells associated with the treatment outcome of neonatal sepsis","volume":"134","author":"Wang","year":"2021","journal-title":"Mol. Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s41698-024-00522-z","article-title":"Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance","volume":"8","author":"Wang","year":"2024","journal-title":"NPJ Precis. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Gao, J., Liang, Y., and Wang, L. (2022). Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.888713"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/annonc\/mdw615","article-title":"Resistance to anticancer immunity in cancer patients: Potential strategies to reverse resistance","volume":"28","author":"Bonavida","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Zhong, Z., Zhang, M., Ning, Y., Mao, G., Li, X., Deng, Q., Chen, X., Zuo, D., Zhao, X., and Xie, E. (2022). Development of a bispecific antibody targeting PD-L1 and TIGIT with optimal cytotoxicity. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-22975-7"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/s41551-021-00800-2","article-title":"Rejuvenation of tumour-specific T cells through bispecific antibodies targeting PD-L1 on dendritic cells","volume":"5","author":"Liu","year":"2021","journal-title":"Nat. Biomed. Eng."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"100800","DOI":"10.1016\/j.medj.2025.100800","article-title":"Immune-related adverse events associated with cancer immunotherapy","volume":"6","author":"Kungwankiattichai","year":"2025","journal-title":"Med"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Ibis, B., Aliazis, K., Cao, C., Yenyuwadee, S., and Boussiotis, V.A. (2023). Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1197364"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Sasikumar, P.G., and Ramachandra, M. (2022). Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.752065"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s40259-018-0303-4","article-title":"Small-Molecule Immune Checkpoint Inhibitors Targeting PD-1\/PD-L1 and Other Emerging Checkpoint Pathways","volume":"32","author":"Sasikumar","year":"2018","journal-title":"BioDrugs"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1784\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T11:56:03Z","timestamp":1763985363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":124,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ph18121784"],"URL":"https:\/\/doi.org\/10.3390\/ph18121784","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]}}}