{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T12:30:07Z","timestamp":1786624207314,"version":"build-2736575974"},"reference-count":31,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"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: Immune exclusion in head and neck squamous cell carcinoma (HNSCC) limits immunotherapy efficacy, yet the molecular determinants of stromal-immune organization remain incompletely characterized. The desmosomal cadherin DSG2 is highly expressed in squamous epithelium; its role in shaping the tumor microenvironment (TME) is unknown. Methods: We integrated bulk RNA-seq from 836 HNSCC patients (TCGA-HNSC n = 566, GSE65858 n = 270), single-cell RNA-seq (GSE139324, n = 26 patients, 133,308 cells), spatial transcriptomics (GSE208253, n = 12), proteomics (CPTAC-HNSCC, n = 108), and external validation cohorts (GSE41613, n = 97). CellChat ligand-receptor analysis, mediation analysis, Mendelian randomization (MR), LASSO-penalized Cox regression, HPV-stratified sensitivity analysis, and transcription factor (TF) correlation analysis were employed. Results: DSG2 exhibited epithelial-specific expression and showed consistent positive correlation with CXCL8 (IL-8; TCGA \u03c1 = 0.228, p = 4.4 \u00d7 10\u22128) and myCAF activation across independent cohorts. Single-cell analysis revealed that 99.5% of CXCL8-producing cells have zero DSG2 expression, establishing the bulk correlation as compositional rather than cell-intrinsic. CellChat identified CXCL8-CXCR2 as the strongest tumor-stroma interaction in DSG2-high regions (probability = 0.821, 1.80-fold enrichment). Mediation analysis demonstrated 43.6% (95% CI [34.3\u201353.6%]) of DSG2\u2019s tissue-level association with myCAF activation is mediated through CXCL8 (compositional mediation). Multi-instrument MR (IVW: Beta = \u22120.028, p = 0.028; I2 = 0.0%) corroborated the compositional model. Protein-level validation in CPTAC-HNSCC confirmed DSG2-CD8A inverse correlation (Spearman \u03c1 = \u22120.35, p = 2.2 \u00d7 10\u22124). Pan-squamous meta-analysis confirmed negative DSG2-cytolytic activity correlations (pooled \u03c1 = \u22120.213, 95% CI [\u22120.296, \u22120.128], I2 = 58.6%, 4 cohorts). DSG2 correlated with TIDE score (\u03c1 = 0.176) and TGF-\u03b2 exclusion subscore (\u03c1 = 0.428). DepMap analysis identified CXCR2 inhibitor collateral sensitivity (\u03c1 = \u22120.408, p &lt; 0.0001). An eight-gene co-expression module was validated in two independent cohorts (GSE41613: HR = 3.09, p = 0.003; GSE65858: HR = 1.57, p = 0.032). Conclusions: DSG2 marks a stromal-immune organizational state characterized by CXCL8-CXCR2 paracrine signaling, myCAF activation, and immune exclusion, conserved across squamous malignancies. DSG2-high\/PD-L1-high tumors (30.4% prevalence) exhibit the worst predicted ICI response and represent a candidate population for biomarker-selected CXCR2 inhibitor trials in combination with anti-PD-1 therapy.<\/jats:p>","DOI":"10.3390\/cancers18162611","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T11:33:46Z","timestamp":1786620826000},"page":"2611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DSG2 Expression Marks a Stromal-Immune Organizational State in Head and Neck Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"\u00d6mer Tar\u0131k","family":"\u00c7i\u00e7ek","sequence":"first","affiliation":[{"name":"School of Medicine, Marmara University, Istanbul 34854, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9544-8830","authenticated-orcid":false,"given":"Muharrem Okan","family":"\u00c7ak\u0131r","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Pharmacy and Chemistry, Kingston University London, London KT1 2EE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beg\u00fcm","family":"Kurt","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Marmara University, Istanbul 34854, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1762-0284","authenticated-orcid":false,"given":"Bet\u00fcl Karademir","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Marmara University, Istanbul 34854, Turkey"},{"name":"Department of Biochemistry, School of Medicine, Recep Tayyip Erdogan University, Rize 53100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-5111","authenticated-orcid":false,"given":"G. Hossein","family":"Ashrafi","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Pharmacy and Chemistry, Kingston University London, London KT1 2EE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"\u00d6zdo\u011fan","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Goztepe Memorial Hospital Cancer Center, Istanbul 34730, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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