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We analyzed a retrospective cohort of primary tumor specimens from 145 patients with synchronous or metachronous metastatic ccRCC to evaluate the expression of B7\u2010H3, B7\u2010H4, B7\u2010H5, and B7\u2010H7 and their association with tumor aggressiveness, treatment response, and long\u2010term survival. Immunohistochemistry revealed marked intratumoral heterogeneity and distinct compartmentalized expression patterns, with B7\u2010H3 detected in both tumor cells and stromal compartments, B7\u2010H4 exclusively expressed in tumor cells, B7\u2010H5 localized to tumor cells and tumor\u2010infiltrating lymphocytes (TILs), and B7\u2010H7 detected in both tumor cells and TILs. We did not detect any overlap in expression between B7\u2010H proteins and PD\u2010L1 positivity in TILs. High B7\u2010H3 expression in tumor and stroma was significantly associated with higher histological grade, increased local invasion, lymph node involvement, and advanced stage. B7\u2010H5 expression in TILs correlated with impaired Eastern Cooperative Oncology Group performance status. Elevated B7\u2010H3 predicted unfavorable response to tyrosine kinase inhibitors, mechanistic target of rapamycin\u00a0inhibitors, and immune checkpoint inhibitors, whereas B7\u2010H5 negativity in tumor cells associated with more favorable treatment outcomes. B7\u2010H4 and B7\u2010H7 expression in tumor cells were associated with features of tumor aggressiveness and immune suppression, further highlighting the potential role of multiple B7\u2010H family checkpoints in metastatic ccRCC. In multivariable Cox regression models, B7\u2010H3 expression in tumor and stroma independently predicted shorter disease\u2010free and overall survival. B7\u2010H5 expression in TILs independently predicted reduced overall survival. These findings identify B7\u2010H3 as a robust biomarker of tumor aggressiveness, therapeutic resistance, and adverse prognosis in metastatic ccRCC, while B7\u2010H5 in TILs provides complementary prognostic information. Integrated profiling of B7\u2010H immune checkpoints in primary tumors may refine clinical risk stratification and support the development of biomarker\u2010guided immunotherapeutic strategies.<\/jats:p>","DOI":"10.1002\/2056-4538.70108","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:33:43Z","timestamp":1784529223000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune checkpoint profiling of\n                    <scp>B7<\/scp>\n                    \u2010H proteins predicts survival and treatment response in metastatic clear cell renal cell carcinoma"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7906-0801","authenticated-orcid":false,"given":"Maite","family":"Emaldi","sequence":"first","affiliation":[{"name":"Department of Cancer Biobizkaia Health Research Institute  Barakaldo Spain"},{"name":"CIBERER, ISCIII  Madrid 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Oncology Group Biogipuzkoa Health Research Institute  San Sebasti\u00e1n Spain"},{"name":"IKERBASQUE, Basque Foundation for Science  Bilbao Spain"},{"name":"Radcliffe Department of Medicine University of Oxford  Oxford UK"},{"name":"Sino\u2010Swiss Institute of Advanced Technology (SSIAT) Shanghai University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9100-248X","authenticated-orcid":false,"given":"Rafael","family":"Pulido","sequence":"additional","affiliation":[{"name":"Department of Cancer Biobizkaia Health Research Institute  Barakaldo Spain"},{"name":"CIBERER, ISCIII  Madrid Spain"},{"name":"IKERBASQUE, Basque Foundation for Science  Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1735-8792","authenticated-orcid":false,"given":"Javier C","family":"Angulo","sequence":"additional","affiliation":[{"name":"Department of Urology Hospital Universitario de Getafe  Getafe Spain"},{"name":"Department of Medicine, Faculty of Medicine, Health and Sports European University of Madrid  Getafe Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0842-5348","authenticated-orcid":false,"given":"Jos\u00e9 I","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Cancer Biobizkaia Health Research Institute  Barakaldo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6744-818X","authenticated-orcid":false,"given":"Gorka","family":"Larrinaga","sequence":"additional","affiliation":[{"name":"Department of Cancer Biobizkaia Health Research Institute  Barakaldo Spain"},{"name":"Department of Nursing, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa Spain"},{"name":"Department of Physiology, Faculty of Medicine and Nursing University of the Basque Country (UPV\/EHU)  Leioa 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