{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T18:08:29Z","timestamp":1788718109859,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lung cancer (LC) is the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) representing 85\u201390% of cases. Despite the efficacy of PD-1\/PD-L1 immune checkpoint inhibitors, primary and acquired resistance highlight the need for novel immunotherapeutic strategies. A systematic review of the literature from 2020 to 2025 was conducted according to the PICO model. Six studies were included, encompassing phase I\u2013III clinical trials. The analysis focused on efficacy, safety, and emerging therapeutic strategies targeting TIGIT in NSCLC. TIGIT blockade enhances cytotoxic T lymphocyte and natural killer (NK) cell activity, strengthening antitumor immunity. Clinical trials, particularly with the monoclonal antibody tiragolumab combined with PD-1\/PD-L1 inhibitors, show promising synergistic effects. Emerging strategies, including bispecific antibodies (e.g., TIGIT\/PD-1 and TIGIT\/PD-L1) and experimental cell therapies, are under investigation to further improve the antitumor response. Anti-TIGIT therapies represent a highly promising approach in NSCLC. While phase III data remain limited, biomarker-driven, well-designed trials are essential. If validated, TIGIT blockade could become a key addition to immuno-oncology treatment strategies for NSCLC.<\/jats:p>","DOI":"10.3390\/ijms26199307","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T15:54:54Z","timestamp":1758642894000},"page":"9307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["TIGIT Expression and Its Implications in Non-Small-Cell Lung Cancer Progression and Therapy: A Systematic Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2211-1413","authenticated-orcid":false,"given":"Julia","family":"Piekarz","sequence":"first","affiliation":[{"name":"Student Academic Group, Department of Clinical Oncology and Chemotherapy, Medical University, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2460-1747","authenticated-orcid":false,"given":"Natalia","family":"Picheta","sequence":"additional","affiliation":[{"name":"Student Academic Group, Department of Clinical Oncology and Chemotherapy, Medical University, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8033-3574","authenticated-orcid":false,"given":"Katarzyna","family":"Szklener","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology and Chemotherapy, Medical University, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9812-0777","authenticated-orcid":false,"given":"S\u0142awomir","family":"Ma\u0144dziuk","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology and Chemotherapy, Medical University, 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.semcancer.2022.06.010","article-title":"Chemokines and NSCLC: Emerging role in prognosis, heterogeneity, and therapeutics","volume":"86","author":"Srivastava","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"539","DOI":"10.3390\/epidemiologia5030037","article-title":"Risk factors and preventive measures for lung cancer in the European Union","volume":"5","author":"Kehrle","year":"2024","journal-title":"Epidemiologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"102274","DOI":"10.1016\/j.canep.2022.102274","article-title":"Risk factors for the development of lung cancer among never smokers: A systematic review","volume":"81","author":"Zhang","year":"2022","journal-title":"Cancer Epidemiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/S1470-2045(23)00444-8","article-title":"Global variations in lung cancer incidence by histological subtype in 2020: A population-based study","volume":"24","author":"Zhang","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s43556-022-00107-x","article-title":"Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer","volume":"3","author":"Wang","year":"2022","journal-title":"Mol. Biomed."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.32471\/exp-oncology.2312-8852.vol-44-no-1.17411","article-title":"Current therapeutic strategies and challenges in NSCLC treatment: A comprehensive review","volume":"44","author":"Kumar","year":"2022","journal-title":"Exp. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s13353-023-00786-4","article-title":"Modern therapies of nonsmall cell lung cancer","volume":"64","author":"Jachowski","year":"2023","journal-title":"J. Appl. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5154","DOI":"10.1038\/s41467-023-40745-5","article-title":"Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype","volume":"14","author":"Hiltbrunner","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13045-022-01325-0","article-title":"Immune checkpoint modulators in cancer immunotherapy: Recent advances and emerging concepts","volume":"15","author":"Wang","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2217735","DOI":"10.1080\/2162402X.2023.2217735","article-title":"Studying TIGIT activity against tumors through the generation of knockout mice","volume":"12","author":"Rishiq","year":"2023","journal-title":"OncoImmunology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2013750","DOI":"10.1080\/19420862.2021.2013750","article-title":"Structural and functional characterization of a monoclonal antibody blocking TIGIT","volume":"14","author":"Jeong","year":"2022","journal-title":"mAbs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101184","DOI":"10.1016\/j.esmoop.2023.101184","article-title":"Anti-TIGIT therapies for solid tumors: A systematic review","volume":"8","author":"Rousseau","year":"2023","journal-title":"ESMO Open"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8104","DOI":"10.1038\/s41467-025-63451-w","article-title":"Structural basis of Fusobacterium nucleatum adhesin Fap2 interaction with receptors on cancer and immune cells","volume":"16","author":"Marongiu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mire\u0219tean, C.C., Iancu, R.I., and Iancu, D.P.T. (2025). LAG3, TIM3 and TIGIT: New targets for immunotherapy and potential associations with radiotherapy. Curr. Oncol., 32.","DOI":"10.3390\/curroncol32040230"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","unstructured":"Krzy\u017canowska, N., Wojas-Krawczyk, K., Milanowski, J., and Krawczyk, P. (2022). Future prospects of immunotherapy in non-small-cell lung cancer patients: Is there hope in other immune checkpoints targeting molecules?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063087"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"ltad009","DOI":"10.1093\/immadv\/ltad009","article-title":"TIGIT-based immunotherapeutics in lung cancer","volume":"3","author":"Patel","year":"2023","journal-title":"Immunother. Adv."},{"key":"ref_18","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_19","first-page":"1430163","article-title":"Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity","volume":"15","author":"Reches","year":"2024","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/s41419-023-05961-3","article-title":"TIGIT, a novel immune checkpoint therapy for melanoma","volume":"14","author":"Tang","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5016","DOI":"10.1038\/s41467-023-40755-3","article-title":"TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation","volume":"14","author":"Worboys","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.immuni.2022.02.005","article-title":"Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses","volume":"55","author":"Banta","year":"2022","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"914406","DOI":"10.3389\/fimmu.2022.914406","article-title":"Emergence of the CD226 axis in cancer immunotherapy","volume":"13","author":"Conner","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1038\/s12276-024-01317-9","article-title":"Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2","volume":"56","author":"Jo","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/s41419-025-07984-4","article-title":"TIGIT in cancer: From mechanism of action to promising immunotherapeutic strategies","volume":"16","author":"Cui","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1007\/s00277-025-06304-2","article-title":"TIGIT\/PVR axis regulates anti-tumor immunity in hematologic malignancies","volume":"104","author":"Meng","year":"2025","journal-title":"Ann. Hematol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1038\/s43018-024-00870-6","article-title":"TIGIT and PD-L1 co-blockade promotes clonal expansion of multipotent, non-exhausted antitumor T cells by facilitating co-stimulation","volume":"5","author":"Nutsch","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e004711","DOI":"10.1136\/jitc-2022-004711","article-title":"TIGIT-CD226-PVR axis: Advancing immune checkpoint blockade for cancer immunotherapy","volume":"10","author":"Chiang","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e128633","DOI":"10.1172\/jci.insight.128633","article-title":"Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade","volume":"5","author":"Lee","year":"2020","journal-title":"JCI Insight"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"403","DOI":"10.5483\/BMBRep.2021.54.8.054","article-title":"Perspectives on immune checkpoint ligands: Expression, regulation, and clinical implications","volume":"54","author":"Moon","year":"2021","journal-title":"BMB Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"911919","DOI":"10.3389\/fimmu.2022.911919","article-title":"TIGIT as a promising therapeutic target in autoimmune diseases","volume":"13","author":"Yue","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s12943-023-01800-3","article-title":"Co-inhibition of TIGIT and PD-1\/PD-L1 in cancer immunotherapy: Mechanisms and clinical trials","volume":"22","author":"Chu","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41571-021-00552-7","article-title":"Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways","volume":"19","author":"Kraehenbuehl","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110358","DOI":"10.1016\/j.intimp.2023.110358","article-title":"TIGIT: An emerging immune checkpoint target for immunotherapy in autoimmune disease and cancer","volume":"120","author":"Zhao","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.semcancer.2022.03.014","article-title":"Immune checkpoint proteins: Signaling mechanisms and molecular interactions in cancer immunotherapy","volume":"86","author":"Gaikwad","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40364-023-00543-z","article-title":"Targeting TIGIT for cancer immunotherapy: Recent advances and future directions","volume":"12","author":"Zhang","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e754","DOI":"10.1002\/ctm2.754","article-title":"PD-L1\/TIGIT bispecific antibody showed survival advantage in animal model","volume":"12","author":"Mu","year":"2022","journal-title":"Clin. Transl. Med."},{"key":"ref_38","first-page":"1","article-title":"Tiragolumab (anti-TIGIT) in SCLC: Skyscraper-02, a towering inferno","volume":"14","author":"Brazel","year":"2023","journal-title":"Lung Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1080\/14796694.2024.2343272","article-title":"The KEYVIBE program: Vibostolimab and pembrolizumab for the treatment of advanced malignancies","volume":"20","author":"Niu","year":"2024","journal-title":"Future Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1158\/1078-0432.CCR-21-2780","article-title":"A phase 1a\/b open-label, dose-escalation study of etigilimab alone or in combination with nivolumab in patients with locally advanced or metastatic solid tumors","volume":"28","author":"Mettu","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5819","DOI":"10.1038\/s41467-025-60757-7","article-title":"Dual TIGIT and PD-1 blockade with domvanalimab plus zimberelimab in hepatocellular carcinoma refractory to anti-PD-1 therapies: The phase 2 LIVERTI trial","volume":"16","author":"Hsiehchen","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.annonc.2021.11.002","article-title":"First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer","volume":"33","author":"Niu","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1001\/jamaoncol.2023.3867","article-title":"Anti-TIGIT antibody tiragolumab alone or with atezolizumab in patients with advanced solid tumors: A phase 1a\/1b nonrandomized controlled trial","volume":"9","author":"Kim","year":"2023","journal-title":"JAMA Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S1470-2045(22)00226-1","article-title":"Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): Primary and follow-up analyses of a randomised, double-blind, phase 2 study","volume":"23","author":"Cho","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"CT051","DOI":"10.1158\/1538-7445.AM2025-CT051","article-title":"SKYSCRAPER-01: A phase III, randomized trial of tiragolumab + atezolizumab versus placebo + atezolizumab in patients with previously-untreated PD-L1-high, locally advanced unresectable\/metastatic NSCLC","volume":"85","author":"Peters","year":"2025","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.1038\/s41598-023-29724-4","article-title":"Prognostic impact of PD-L1 and TIGIT expression in non-small cell lung cancer following concurrent chemo-radiotherapy","volume":"13","author":"Mori","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cllc.2023.12.010","article-title":"STAR-121: A phase III randomized study of domvanalimab and zimberelimab in combination with chemotherapy versus pembrolizumab with chemotherapy in untreated metastatic non\u2013small cell lung cancer with no actionable gene alterations","volume":"25","author":"Gray","year":"2024","journal-title":"Clin. Lung Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"13922","DOI":"10.3389\/abp.2025.13922","article-title":"Advancements in single-cell RNA sequencing and spatial transcriptomics: Transforming biomedical research","volume":"72","author":"Birhanu","year":"2025","journal-title":"Acta Biochim. Pol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:48:27Z","timestamp":1760035707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,23]]},"references-count":48,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199307"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199307","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,23]]}}}