{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:03:12Z","timestamp":1784167392557,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Clear cell renal cell carcinoma (ccRCC), the predominant malignant subtype of kidney cancer, is the leading cause of death among renal cell carcinoma patients. Although a subset of ccRCC patients benefit from select immune checkpoint inhibitors (ICIs), prognosis remains poor. While PD-1 and PD-L1 have been extensively studied, the prevalence and distribution of other immune checkpoints (ICs) and their relationship with epithelial-to-mesenchymal transition (EMT) remain poorly characterised. Here, we investigated the interplay between twenty ICs and EMT markers and assessed their combined prognostic relevance in ccRCC patients. Methods: Transcriptomic profiling and integrated bioinformatic analyses were performed, including differential expression, correlation analyses, survival analyses, forest plot analyses, ROC curve evaluation, and OncoPrint visualisation, complemented by analysis of single-cell RNA sequencing data, immunohistochemistry, and multiplex secretory IC (LegendPlex) assays. Results: Transcriptomic profiling of over 500 ccRCC tumours versus normal kidney tissue revealed dysregulation of ICs, particularly LAG3 and NT5E. Notably, expression of ICs, including LAG3 and NT5E, was associated with poor overall survival in 415 ccRCC patients. ICs that synergised with the EMT phenotype provided improved prognostic discrimination compared to individual ICs. Correlation analyses, single-cell RNA sequencing, and immunohistochemistry demonstrated an association between EMT-associated tumours and expression of LAG3 and NT5E. ROC analysis indicated modest prognostic performance of LAG3 and NT5E. Conclusions: Collectively, this study identifies an EMT\u2013IC axis in ccRCC and demonstrates its relevance to tumour biology and patient outcomes, highlighting LAG3 and NT5E as potential prognostic markers and therapeutic targets that warrant further investigation.<\/jats:p>","DOI":"10.3390\/cancers18142258","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:05:58Z","timestamp":1784077558000},"page":"2258","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interplay Between Immune Checkpoint Modulators and the Epithelial-to-Mesenchymal Transition Axis in Clear Cell Renal Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Arpita","family":"Poddar","sequence":"first","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University, Ballarat, VIC 3350, Australia"},{"name":"Ian Potter NanoBiosensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC 3000, Australia"},{"name":"Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Ahmady-Nield","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revati","family":"Sharma","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seemadri","family":"Subhadarshini","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Indian Institute of Science, Bengaluru 560012, Karnataka, India"},{"name":"Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-2109","authenticated-orcid":false,"given":"Mohit Kumar","family":"Jolly","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Indian Institute of Science, Bengaluru 560012, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Ramakrishna","sequence":"additional","affiliation":[{"name":"Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea"},{"name":"College of Medicine, Hanyang University, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Raza","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1537-9637","authenticated-orcid":false,"given":"Ravi","family":"Shukla","sequence":"additional","affiliation":[{"name":"Ian Potter NanoBiosensing Facility, NanoBiotechnology Research Laboratory, School of Science, RMIT University, Melbourne, VIC 3000, Australia"},{"name":"Centre for Advanced Materials and Industrial Chemistry, RMIT University, Melbourne, VIC 3001, Australia"},{"name":"School of Health & Biomedical Science, RMIT University, Melbourne, VIC 3000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6880-9795","authenticated-orcid":false,"given":"George","family":"Kannourakis","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Jayachandran","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashanth","family":"Prithviraj","sequence":"additional","affiliation":[{"name":"Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia"},{"name":"Institute of Innovation, Science and Sustainability, Federation University, Ballarat, VIC 3350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41581-024-00820-6","article-title":"Chronic kidney disease and the global public health agenda: An international 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