{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:59:43Z","timestamp":1792789183135,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Rijeka","award":["uniri-iskusni-biomed-23-202"],"award-info":[{"award-number":["uniri-iskusni-biomed-23-202"]}],"id":[{"id":"https:\/\/ror.org\/05r8dqr10","id-type":"ROR","asserted-by":"crossref"}]},{"name":"University of Rijeka","award":["uniri-iz-25\u2013234"],"award-info":[{"award-number":["uniri-iz-25\u2013234"]}],"id":[{"id":"https:\/\/ror.org\/05r8dqr10","id-type":"ROR","asserted-by":"crossref"}]},{"award":["uniri-iskusni-biomed-23-202"],"award-info":[{"award-number":["uniri-iskusni-biomed-23-202"]}],"id":[{"id":"https:\/\/ror.org\/05r8dqr10","id-type":"ROR","asserted-by":"publisher"}]},{"award":["uniri-iz-25\u2013234"],"award-info":[{"award-number":["uniri-iz-25\u2013234"]}],"id":[{"id":"https:\/\/ror.org\/05r8dqr10","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Despite therapeutic advances, laryngeal squamous cell carcinoma (LSCC) remains a clinical challenge. We investigated immune microenvironment remodeling and its prognostic relevance during laryngeal carcinogenesis. Methods: This retrospective study included 227 patients: 45 with benign laryngeal polyps, 55 with laryngeal epithelial dysplasia, and 127 with LSCC; 55 (43.3%) LSCCs were Union for International Cancer Control (UICC) stage I\u2013II and 72 (56.7%) stage III\u2013IV. Immunohistochemistry on tissue microarrays (TMAs) was used to assess the density of cluster of differentiation (CD)4-, CD8-, forkhead box P3 (FOXP3)-, programmed cell death protein 1 (PD-1)-, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-, CD68-, and CD163-positive immune cells, together with FOXP3\/CTLA-4 double-positive cells. Immune-cell densities were expressed as the percentage of the respective intraepithelial\/intratumoral or stromal compartment occupied by positively stained immune cells. An exploratory Protective Immune Score (PIS; 0\u20132) assigned one point each for high intraepithelial FOXP3 and high stromal CTLA-4 cell density. Results: LSCC showed increased stromal immune-cell density and coordinated immune organization. Stromal PD-1 correlated with CD4, CD8, and FOXP3 density (rs = 0.561, 0.515, and 0.403), and stromal CTLA-4 with FOXP3 (rs = 0.556; all p &lt; 0.0001). High intraepithelial FOXP3 was associated with improved disease-specific survival (DSS; hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10\u20130.72) and disease-free survival (DFS; HR = 0.24, 95% CI 0.10\u20130.59). High stromal CTLA-4 similarly favored DSS (HR = 0.29, 95% CI 0.11\u20130.74) and DFS (HR = 0.26, 95% CI 0.11\u20130.61). The PIS remained independently associated with DSS (adjusted HR = 0.29, 95% CI 0.16\u20130.55) and DFS (adjusted HR = 0.29, 95% CI 0.17\u20130.52). Conclusions: Laryngeal carcinogenesis is characterized by progressive, compartment-specific immune remodeling, with the stroma emerging as the principal site of coordinated immune organization. The PIS captures spatially defined favorable immune features and warrants validation in independent cohorts.<\/jats:p>","DOI":"10.3390\/cancers18193130","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:00:34Z","timestamp":1790589634000},"page":"3130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Remodeling of the Immune Microenvironment During Laryngeal Carcinogenesis Reveals Prognostic Immune Patterns in Laryngeal Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Toni","family":"Vidovi\u0107","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia"},{"name":"Faculty of Medicine, University of Rijeka, 51000 Rijeka, 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Croatia"},{"name":"Clinical Department of Pathology and Cytology, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1787-2177","authenticated-orcid":false,"given":"Emina","family":"Babarovi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"},{"name":"Clinical Department of Pathology and Cytology, Clinical Hospital Center Rijeka, 51000 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