{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:40:45Z","timestamp":1792190445284,"version":"4.4.0"},"reference-count":109,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Immune checkpoint inhibitor-related pneumonitis (CIP) is an uncommon but clinically relevant toxicity in renal cell carcinoma (RCC), where immune checkpoint inhibitors are frequently used either as dual immunotherapy or in combination with VEGF-targeted tyrosine kinase inhibitors. In RCC, CIP poses specific diagnostic challenges because respiratory symptoms and computed tomography findings may overlap with pulmonary metastases, infections, thromboembolic events, heart failure, and TKI-related lung toxicity. This review summarizes the incidence of CIP across pivotal RCC trials and real-world cohorts, compares its epidemiology with non-small cell lung cancer, and discusses clinical presentation, radiological patterns, differential diagnosis, and current management strategies. Particular attention is given to RCC-specific mechanisms, including immune-mediated alveolar injury, T cell activation, cytokine dysregulation, macrophage activation, GSDME-mediated pyroptosis, and the potential contribution of VEGF pathway inhibition to pulmonary inflammation. We also review risk factors, steroid-refractory disease, second-line immunosuppression, and the unresolved issue of ICI rechallenge after pneumonitis. A better understanding of these mechanisms and clinical features may improve early recognition, guide multidisciplinary management, and support safer use of immunotherapy-based combinations in patients with RCC.<\/jats:p>","DOI":"10.3390\/biom16081117","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:00Z","timestamp":1785428100000},"page":"1117","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Immune Checkpoint Inhibitor-Related Pneumonitis in Renal Cell Carcinoma: Clinical Features, Mechanisms, and Lessons from Lung Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Kristian","family":"Shtembari","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1856-2848","authenticated-orcid":false,"given":"Martina","family":"Catalano","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9594-1451","authenticated-orcid":false,"given":"Ismaela Anna","family":"Vascotto","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Calandrelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Mancini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6907-8682","authenticated-orcid":false,"given":"Luca","family":"Pratesi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Izzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinella Micol","family":"Mela","sequence":"additional","affiliation":[{"name":"Clinical Oncology, Careggi University Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8524-4033","authenticated-orcid":false,"given":"Virginia","family":"Rossi","sequence":"additional","affiliation":[{"name":"Clinical Oncology, Careggi University Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8861-8718","authenticated-orcid":false,"given":"Serena","family":"Pillozzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejo","family":"Rodriguez-Vida","sequence":"additional","affiliation":[{"name":"Hospital del Mar, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9993-9664","authenticated-orcid":false,"given":"Mohamed","family":"Aseafan","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, Department of Internal Medicine, Security Forces Hospital, Riyadh 11481, Saudi Arabia"},{"name":"College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5606-6434","authenticated-orcid":false,"given":"Maria Tereza","family":"Nieto-Coronel","sequence":"additional","affiliation":[{"name":"Oncopalia, MyA Center, Medical Oncology Departament, La Paz City P.O. Box 8635, Bolivia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Santoni","sequence":"additional","affiliation":[{"name":"Oncology Unit, Macerata Hospital, 62100 Macerata, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Antonuzzo","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy"},{"name":"Clinical Oncology, Careggi University Hospital, 50134 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5504-8237","authenticated-orcid":false,"given":"Giandomenico","family":"Roviello","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","unstructured":"National Comprehensive Cancer Network (2020, June 22). NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer (Version 2.2020). Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/kidney.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S0140-6736(24)00917-6","article-title":"Renal cell carcinoma","volume":"404","author":"Young","year":"2024","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zhuang, T.Z., Case, K., Olsen, T.A., Brown, J.T., Carthon, B.C., Kucuk, O., Goldman, J., Harris, W., Bilen, M.A., and Nazha, B. (2022). Metastatic Clear-Cell Renal Cell Carcinoma in the Era of Immune Checkpoint Inhibitors: Therapies and Ongoing Trials. Cancers, 14.","DOI":"10.3390\/cancers14122867"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1056\/NEJMoa2035716","article-title":"Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma","volume":"384","author":"Motzer","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1056\/NEJMoa1816714","article-title":"Pembrolizumab Plus Axitinib Versus Sunitinib for Advanced Renal-Cell Carcinoma","volume":"380","author":"Rini","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1056\/NEJMoa2026982","article-title":"Nivolumab Plus Cabozantinib Versus Sunitinib for Advanced Renal-Cell Carcinoma","volume":"384","author":"Choueiri","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1056\/NEJMoa1712126","article-title":"Nivolumab Plus Ipilimumab Versus Sunitinib in Advanced Renal-Cell Carcinoma","volume":"378","author":"Motzer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1200\/JCO.2017.77.6385","article-title":"Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline","volume":"36","author":"Brahmer","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1056\/NEJMra1703481","article-title":"Immune-Related Adverse Events Associated with Immune Checkpoint Blockade","volume":"378","author":"Postow","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.chest.2021.02.032","article-title":"Immune Checkpoint Inhibitor-Related Pneumonitis in Lung Cancer","volume":"160","author":"Atchley","year":"2021","journal-title":"Chest"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1065","DOI":"10.1093\/oncolo\/oyad118","article-title":"Incidence and Risk Factors for Pneumonitis Associated with Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: A Single Center Experience","volume":"28","author":"Altan","year":"2023","journal-title":"Oncologist"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3892\/ijo.2023.5570","article-title":"Anti-PD-1\/PD-L1 and anti-CTLA-4 associated checkpoint inhibitor pneumonitis in non-small cell lung cancer: Occurrence, pathogenesis and risk factors","volume":"63","author":"Hu","year":"2023","journal-title":"Int. J. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1097\/PAS.0000000000001298","article-title":"Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related Pneumonitis","volume":"43","author":"Larsen","year":"2019","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Casal, A., Leiro-Fern\u00e1ndez, V., Villar-Aguilar, L., Casal-Guisande, M., Mosteiro-A\u00f1\u00f3n, M., Botana-Rial, M., Represas-Represas, C., Torres-Dur\u00e1n, M., and Fern\u00e1ndez-Villar, A. (2025). Lung Toxicity from Immune Checkpoint Inhibitors: A Diagnostic Approach. J. Clin. Med., 14.","DOI":"10.3390\/jcm14176133"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2239","DOI":"10.1002\/onco.13940","article-title":"The Inconsistent and Inadequate Reporting of Immune-Related Adverse Events in PD-1\/PD-L1 Inhibitors: A Systematic Review of Randomized Controlled Clinical Trials","volume":"26","author":"Xie","year":"2021","journal-title":"Oncologist"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1002\/ijc.70267","article-title":"Real-world efficacy and toxicity of ipilimumab and nivolumab as a first-line treatment for advanced renal cell carcinoma according to IMDC risk criteria\u2014A multi-center retrospective analysis on behalf of the GUARDIANS group","volume":"158","author":"Dinkel","year":"2025","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/s41698-025-01123-0","article-title":"A real-world cohort study of immune-related adverse events in patients receiving immune checkpoint inhibitors","volume":"9","author":"Wang","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1056\/NEJMoa1816047","article-title":"Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma","volume":"380","author":"Motzer","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Su, Q., Zhu, E.C., Wu, J.-B., Li, T., Hou, Y.-L., Wang, D.-Y., and Gao, Z.-H. (2019). Risk of Pneumonitis and Pneumonia Associated with Immune Checkpoint Inhibitors for Solid Tumors: A Systematic Review and Meta-Analysis. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00108"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.annonc.2024.12.008","article-title":"Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: Final analysis of the phase III JAVELIN Renal 101 trial","volume":"36","author":"Choueiri","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tapiavala, S., Luo, C., Shenouda, M., Patel, V., and Davis, A.A. (2025). Reporting of immune-related adverse events in US Food and Drug Administration approvals of immune checkpoint inhibitors. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1606599"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/ijc.32132","article-title":"A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors","volume":"145","author":"Maillet","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1001\/jamaoncol.2016.2453","article-title":"Incidence of Programmed Cell Death 1 Inhibitor\u2013Related Pneumonitis in Patients with Advanced Cancer: A Systematic Review and Meta-analysis","volume":"2","author":"Nishino","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"102333","DOI":"10.1016\/j.ctrv.2021.102333","article-title":"Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review","volume":"103","author":"McGregor","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1200\/JCO.2016.68.2005","article-title":"Pneumonitis in Patients Treated with Anti\u2013Programmed Death-1\/Programmed Death Ligand 1 Therapy","volume":"35","author":"Naidoo","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.chest.2017.04.177","article-title":"Incidence of Pneumonitis with Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials","volume":"152","author":"Khunger","year":"2017","journal-title":"Chest"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"O\u2019rEilly, D., O\u2019lEary, C.L., Reilly, A., Teo, M.Y., O\u2019kAne, G., Hendriks, L., Bennett, K., and Naidoo, J. (2024). Toxicity of immune checkpoint inhibitors and tyrosine kinase inhibitor combinations in solid tumours: A systematic review and meta-analysis. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1380453"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"111884","DOI":"10.1016\/j.intimp.2024.111884","article-title":"Immune-related adverse events associated with first-line immune checkpoint inhibitors for metastatic renal cell carcinoma: A systematic review and network meta-analysis","volume":"131","author":"Wang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"346","DOI":"10.21873\/invivo.13834","article-title":"Evaluation of Lung Adverse Events Associated with Lenvatinib: A Post-marketing Surveillance Study","volume":"39","author":"Kanbayashi","year":"2024","journal-title":"In Vivo"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e16533","DOI":"10.1200\/JCO.2022.40.16_suppl.e16533","article-title":"Toxicities of anti-VEGF therapies used in metastatic renal cell carcinoma: A real-world experience","volume":"40","author":"Master","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Li, S., Geng, Z., Hong, S., Zhang, J., Yang, Y., Wei, Q., Zhang, X., Zhuang, X., Huo, R., and Han, S. (2025). Advances in the mechanisms, imaging characteristics and management strategies for immune checkpoint inhibitor-related pneumonitis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1656063"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2217\/fon-2022-0826","article-title":"Immune-induced pneumonia in patients with advanced solid tumors treated with immunotherapy: A real-world assessment","volume":"19","author":"Wang","year":"2023","journal-title":"Futur. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1159\/000509941","article-title":"Immune Checkpoint Inhibitor-Related Pneumonitis","volume":"99","author":"Gomatou","year":"2020","journal-title":"Respiration"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1159\/000526141","article-title":"Risk Factors for Immune Checkpoint Inhibitor-Related Pneumonitis in Cancer Patients: A Systemic Review and Meta-Analysis","volume":"101","author":"Zhou","year":"2022","journal-title":"Respiration"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Allen, E., Umoru, G., Ajewole, V., and Bernicker, E. (2023). Incidence and outcome of immune checkpoint-induced pneumonitis in oncology patients with history of pulmonary disease. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1283360"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1097\/MCP.0000000000000975","article-title":"Immunotherapy-related pneumonitis and the synergic impact of thoracic radiation and preexisting interstitial lung disease","volume":"29","author":"Azhar","year":"2023","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1148\/radiol.2021203427","article-title":"Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper from the Fleischner Society","volume":"298","author":"Johkoh","year":"2021","journal-title":"Radiology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1200\/JCO.21.01440","article-title":"Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update","volume":"39","author":"Schneider","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s00262-025-04053-9","article-title":"Clinical characteristics, outcomes, and predictive modeling of patients diagnosed with immune checkpoint inhibitor therapy-related pneumonitis","volume":"74","author":"Hazim","year":"2025","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kong, Y., Hong, L., Xu, X.-C., Chen, Y.-F., and Xu, J. (2024). The relative risk of immune checkpoint inhibitor pneumonitis in advanced non-small- cell lung cancer: Meta-analyses of controlled clinical trials. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0301931"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1007\/s00228-020-03083-9","article-title":"Incidence risk of PD-1\/PD-L1\u2013related pneumonia and diarrhea in non-small cell lung cancer (NSCLC) patients: A systematic review and meta-analysis of randomized controlled trials","volume":"77","author":"Tong","year":"2021","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Guo, X., Chen, S., Wang, X., and Liu, X. (2023). Immune-related pulmonary toxicities of checkpoint inhibitors in non-small cell lung cancer: Diagnosis, mechanism, and treatment strategies. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1138483"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1001\/jama.2024.12848","article-title":"Renal Cell Carcinoma: A Review","volume":"332","author":"Rose","year":"2024","journal-title":"JAMA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1001\/jamaoncol.2016.1051","article-title":"Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors","volume":"2","author":"Friedman","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zhu, S., Fu, Y., Zhu, B., Zhang, B., and Wang, J. (2020). Pneumonitis Induced by Immune Checkpoint Inhibitors: From Clinical Data to Translational Investigation. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.01785"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1111\/his.14704","article-title":"Immune check-point inhibitor-related pneumonitis: Acute lung injury with rapid progression and organising pneumonia with less severe clinical disease","volume":"81","author":"Imran","year":"2022","journal-title":"Histopathology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"102718","DOI":"10.1016\/j.ctrv.2024.102718","article-title":"The more the merrier? Evidence and efficacy of immune checkpoint- and tyrosine kinase inhibitor combinations in advanced solid cancers","volume":"125","author":"Starzer","year":"2024","journal-title":"Cancer Treat. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1056\/NEJMoa2212851","article-title":"Cabozantinib Plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma","volume":"388","author":"Choueiri","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Huang, J., Chen, X., Xia, B., and Ma, S. (2023). Advances in CT features and radiomics of checkpoint inhibitor-related pneumonitis: A short review. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1082980"},{"key":"ref_51","unstructured":"Kalisz, K.R., Ramaiya, N.H., Laukamp, K.R., and Gupta, A. (2018, January 25\u201330). Immune Checkpoint Inhibitor Therapy\u2013Related Pneumonitis: Patterns and Management. Proceedings of the 104th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America (RSNA), Chicago, IL, USA."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6051","DOI":"10.1158\/1078-0432.CCR-16-1320","article-title":"PD-1 Inhibitor\u2013Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course","volume":"22","author":"Nishino","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"20200409","DOI":"10.1259\/bjr.20200409","article-title":"Clinical and radiological features of immune checkpoint inhibitor-related pneumonitis in lung cancer and non-lung cancers","volume":"93","author":"Nobashi","year":"2020","journal-title":"Br. J. Radiol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Zhou, X., Xu, Y., Ying, Y., Chen, R., Wang, Z., and Lv, X. (2025). Risk factors for checkpoint inhibitor pneumonitis in lung cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1607170"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Berz, A.M., Boughdad, S., Vietti-Violi, N., Digklia, A., Dromain, C., Dunet, V., and Duran, R. (2023). Imaging assessment of toxicity related to immune checkpoint inhibitors. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1133207"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1038\/s41388-023-02805-4","article-title":"Deciphering pathogenic cellular module at single-cell resolution in checkpoint inhibitor-related pneumonitis","volume":"42","author":"Cui","year":"2023","journal-title":"Oncogene"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11645","DOI":"10.1038\/s41467-025-66509-x","article-title":"Uncovering the immune mechanisms underlying the emergence of immunotherapy-induced pneumonitis in lung cancer patients","volume":"16","author":"Lin","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1097\/RCT.0000000000001643","article-title":"High-Resolution CT Patterns of Anti-PD1 Checkpoint Inhibitor-Related Pneumonitis in Patients with Lung Cancer","volume":"48","author":"Pan","year":"2024","journal-title":"J. Comput. Assist. Tomogr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/s41698-024-00715-6","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with immune checkpoint inhibitor-related pneumonitis","volume":"8","author":"Zhang","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41419-024-07319-9","article-title":"Anti-PD-1 exacerbates bleomycin-induced lung injury through GSDME-mediated pyroptosis","volume":"16","author":"Wang","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6640","DOI":"10.1038\/s41467-024-50996-5","article-title":"Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation","volume":"15","author":"Sun","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e005323","DOI":"10.1136\/jitc-2022-005323","article-title":"Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis","volume":"10","author":"Franken","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4305","DOI":"10.1172\/JCI128654","article-title":"The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis","volume":"129","author":"Suresh","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8019","DOI":"10.1007\/s00432-023-04696-0","article-title":"Characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for immune checkpoint inhibitor-related pneumonitis","volume":"149","author":"Wang","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Lin, X., Deng, J., Deng, H., Yang, Y., Sun, N., Zhou, M., Qin, Y., Xie, X., Li, S., and Zhong, N. (2022). Comprehensive Analysis of the Immune Microenvironment in Checkpoint Inhibitor Pneumonitis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.818492"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/s12276-021-00649-0","article-title":"Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms","volume":"53","author":"Kang","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Singh, K.P., Singh, A., Wolkenhauer, O., and Gupta, S.K. (2024). Regulatory Role of IL6 in Immune-Related Adverse Events during Checkpoint Inhibitor Treatment in Melanoma. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202409.0006.v1"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ejca.2022.05.021","article-title":"Human leucocyte antigen genotype association with the development of immune-related adverse events in patients with non-small cell lung cancer treated with single agent immunotherapy","volume":"172","author":"Abed","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Correale, P., Saladino, R.E., Giannarelli, D., Sergi, A., Mazzei, M.A., Bianco, G., Giannicola, R., Iuliano, E., Forte, I.M., and Calandruccio, N.D. (2020). HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis. Cells, 9.","DOI":"10.3390\/cells9091964"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"218168","DOI":"10.1016\/j.canlet.2025.218168","article-title":"A two-stage genome-wide association study to identify novel genetic loci associated with irAEs in lung cancer patients receiving PD-1\/PD-L1 inhibitors","volume":"639","author":"She","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ejca.2023.01.034","article-title":"Immunogenetic variations predict immune-related adverse events for PD-1\/PD-L1 inhibitors","volume":"184","author":"Xin","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e012444","DOI":"10.1136\/jitc-2025-012444","article-title":"Metagenomic next-generation sequencing unraveled the characteristic of lung microbiota in patients with checkpoint inhibitor pneumonitis: Results from a prospective cohort study","volume":"13","author":"Zhou","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"105267","DOI":"10.1016\/j.ebiom.2024.105267","article-title":"The potential role of lung microbiota and lauroylcarnitine in T-cell activation associated with checkpoint inhibitor pneumonitis","volume":"106","author":"Yu","year":"2024","journal-title":"EBioMedicine"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Chen, J., Xu, Q., Zhang, L., Zhang, D., and Wu, X. (2025). Enrichment of prevotella melaninogenica in the lower respiratory tract links to checkpoint inhibitor pneumonitis and radiation pneumonitis. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1594460"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Sumimoto, H., Noda, S., Koide, H., Douke, Y., Sakai, K., Nishikawa, A., Tomioka, A., Hori, M., Nakato, H., and Kimura, Y. (2024). Pre-existing autoimmune disease as a risk factor for immune-related adverse events in cancer patients receiving immune checkpoint inhibitors. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0306995"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1200\/JCO.2022.40.16_suppl.2554","article-title":"Auto-reactive antibodies as predictive markers for immune checkpoint\u2013induced pneumonitis","volume":"40","author":"Altan","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_77","first-page":"6515","article-title":"Association of pre-existing lung interstitial changes with immune-related pneumonitis in patients with non-small lung cancer receiving immunotherapy","volume":"30","author":"Chen","year":"2022","journal-title":"Support. Care Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e1822","DOI":"10.1002\/onco.13900","article-title":"Radiation Versus Immune Checkpoint Inhibitor Associated Pneumonitis: Distinct Radiologic Morphologies","volume":"26","author":"Chen","year":"2021","journal-title":"Oncologist"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Xu, H., Tu, B., Li, H., and Shan, Y. (2025). From chronic inflammation to immune escape: Mapping the tumor microenvironment evolution in renal cell carcinoma. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1683844"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Wen, H., Zheng, S., Zhu, X., Wang, L., and Chen, D. (2025). Characteristics of the tumor microenvironment and potential immunotherapy strategies in renal cell carcinoma. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1643533"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/s41581-020-0316-3","article-title":"The immunology of renal cell carcinoma","volume":"16","author":"Rini","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Shapiro, D.D., Dolan, B., Laklouk, I.A., Rassi, S., Lozar, T., Emamekhoo, H., Wentland, A.L., Lubner, M.G., and Abel, E.J. (2023). Understanding the Tumor Immune Microenvironment in Renal Cell Carcinoma. Cancers, 15.","DOI":"10.3390\/cancers15092500"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Hah, Y.-S., and Koo, K.-C. (2021). Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094452"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Hong, B., Du, B., Chen, R., Zheng, C., Ni, R., Liu, M., and Yang, J. (2024). Comparison of immune checkpoint inhibitors related to pulmonary adverse events: A retrospective analysis of clinical studies and network meta-analysis. BMC Med., 22.","DOI":"10.1186\/s12916-024-03285-3"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Sun, Y.-M., Li, W., Chen, Z.-Y., and Wang, Y. (2021). Risk of Pneumonitis Associated with Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Network Meta-Analysis. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.651553"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1080\/14740338.2023.2193392","article-title":"Tyrosine kinase inhibitors-associated interstitial lung disease used in non-small cell lung cancer: A pharmacovigilance analysis based on the FDA adverse event reporting system database","volume":"22","author":"Zhang","year":"2023","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1007\/s40264-016-0450-9","article-title":"Tyrosine Kinase Inhibitor-Induced Interstitial Lung Disease: Clinical Features, Diagnostic Challenges, and Therapeutic Dilemmas","volume":"39","author":"Shah","year":"2016","journal-title":"Drug Saf."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Fujiwara, Y., Shimomura, K., Yamaguchi, T., Shimizu, J., Watanabe, N., Matsuzawa, R., Murotani, K., and Horio, Y. (2024). The incidence of drug-induced interstitial lung disease caused by epidermal growth factor receptor tyrosine kinase inhibitors or immune checkpoint inhibitors in patients with non-small cell lung cancer in presence and absence of vascular endothelial growth factor inhibitors: A systematic review. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1419256"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Barratt, S.L., Flower, V.A., Pauling, J.D., and Millar, A.B. (2018). VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051269"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"E579","DOI":"10.1161\/CIR.0000000000000641","article-title":"Cardio-Oncology: Vascular and Metabolic Perspectives: A Scientific Statement From the American Heart Association","volume":"139","author":"Campia","year":"2019","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"17137","DOI":"10.1038\/s41598-024-66768-6","article-title":"The application of bronchoscopy in the assessment of immune checkpoint inhibitor-related pneumonitis severity and recurrence","volume":"14","author":"Guo","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Mir, M., Soto, F., Gomez, P.A.A., Arroyo, R.D.R., Suresh, A., Su, A., Gan, Q., Stewart, J., Adachi, R., and Balachandran, D.D. (2025). Bronchoalveolar lavage cell percentages as diagnostic markers of immune checkpoint inhibitor pneumonitis. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1646108"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"22246","DOI":"10.1073\/pnas.1908079116","article-title":"Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities","volume":"116","author":"Tahir","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Ma, K., Lu, Y., Jiang, S., Tang, J., Li, X., and Zhang, Y. (2018). The Relative Risk and Incidence of Immune Checkpoint Inhibitors Related Pneumonitis in Patients with Advanced Cancer: A Meta-Analysis. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01430"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Sammarco, E., Manfredi, F., Nuzzo, A., Ferrari, M., Bonato, A., Salfi, A., Serafin, D., Zatteri, L., Antonuzzo, A., and Galli, L. (2023). Immune Checkpoint Inhibitor Rechallenge in Renal Cell Carcinoma: Current Evidence and Future Directions. Cancers, 15.","DOI":"10.3390\/cancers15123172"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e006982","DOI":"10.1136\/jitc-2023-006982","article-title":"Risk factors and immunomodulators use in steroid-refractory checkpoint inhibitor pneumonitis","volume":"11","author":"Li","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_97","unstructured":"National Comprehensive Cancer Network (2026, June 28). NCCN Clinical Practice Guidelines in Oncology: Management of Immune Checpoint Inhibitor-Related Toxicites. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/ici_tox.pdf."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/resp.13915","article-title":"Pulmonary toxicity of systemic lung cancer therapy","volume":"25","author":"Long","year":"2020","journal-title":"Respirology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e007056","DOI":"10.1136\/jitc-2023-007056","article-title":"Six-week oral prednisolone therapy for immune-related pneumonitis: A single-arm phase II study","volume":"11","author":"Karayama","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1634\/theoncologist.2018-0241","article-title":"Managing Pulmonary Toxicities Associated with Immunotherapy: A Case Discussion","volume":"24","author":"Reed","year":"2019","journal-title":"Oncologist"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"9103","DOI":"10.1200\/JCO.2021.39.15_suppl.9103","article-title":"Chronic immune checkpoint inhibitor (ICI) pneumonitis in patients (pts) with non-small cell lung cancer (NSCLC)","volume":"39","author":"Stuart","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Lai, K.-C., Hsiao, Y.-H., and Chen, S.-C. (2022). Pulse corticosteroid therapy in the treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis: Case report and review. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.994064"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e007409","DOI":"10.1136\/jitc-2023-007409","article-title":"Corticosteroid-resistant immune-related adverse events: A systematic review","volume":"12","author":"Daetwyler","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e001731","DOI":"10.1136\/jitc-2020-001731","article-title":"Steroid-refractory PD-(L)1 pneumonitis: Incidence, clinical features, treatment, and outcomes","volume":"9","author":"Balaji","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e001884","DOI":"10.1136\/jitc-2020-001884","article-title":"Success and failure of additional immune modulators in steroid-refractory\/resistant pneumonitis related to immune checkpoint blockade","volume":"9","author":"Beattie","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.jtho.2021.06.024","article-title":"Beyond Steroids: Immunosuppressants in Steroid-Refractory or Resistant Immune-Related Adverse Events","volume":"16","author":"Luo","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"114028","DOI":"10.1016\/j.ejca.2024.114028","article-title":"Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors","volume":"203","author":"Ruf","year":"2024","journal-title":"Eur. J. Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.7150\/jca.87335","article-title":"The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events due to Immune Checkpoint Inhibitors: A Systematic Review","volume":"14","author":"Machado","year":"2023","journal-title":"J. Cancer"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e013776","DOI":"10.1136\/jitc-2025-013776","article-title":"Steroid-sparing strategies for managing immune-related adverse events","volume":"14","author":"Huang","year":"2026","journal-title":"J. Immunother. Cancer"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1117\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:20:56Z","timestamp":1785428456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/8\/1117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":109,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["biom16081117"],"URL":"https:\/\/doi.org\/10.3390\/biom16081117","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}