{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T06:24:19Z","timestamp":1787293459293,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Head and neck squamous cell carcinoma (HNSCC) comprises biologically diverse tumors, and durable responses to immune-checkpoint blockade are achieved by only a subset of patients. There remains a need for markers that connect clinical outcome with malignant-cell phenotypes and tissue-level immune organization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated The Cancer Genome Atlas HNSCC cohort (TCGA-HNSC), five Gene Expression Omnibus (GEO) validation cohorts, single-cell RNA sequencing, Visium spatial transcriptomics, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq)-informed protein-potential inference, pharmacogenomic screening, genetic-risk analysis and experimental validation. A reconstructed 296-pipeline survival modelling framework was used to prioritize prognostic hub genes across validation-cohort-specific analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SIRPG was repeatedly ranked among the top ten selected genes in all five validation cohorts. At single-cell resolution, SIRPG-high tumor cells showed stronger malignant-cell features, immune-inhibitory and metabolic programs, Scissor-positive risk association, CLCA2\/P53-related perturbation signals and inferred SIRPG-CD47\/signal regulatory protein (SIRP) communication. Spatial analyses placed this axis within an immune-checkpoint-coupled niche, supported by Maxspin\/multiview intercellular spatial modelling (MISTy) spatial coupling, communication analysis by optimal transport (COMMOT)-inferred CD47-SIRPG communication and scProTrans-inferred CD47\/SIRPG protein-potential overlap. Functionally, SIRPG knockdown reduced HNSCC cell viability and increased apoptosis, whereas re-expression of short hairpin RNA (shRNA)-resistant SIRPG restored the CLCA2-BAX\/BCL2 protein response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together, these findings identify SIRPG as an immune-related prognostic hub and context-dependent tumor-cell regulator associated with apoptosis, immune communication and spatial microenvironmental organization in HNSCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1835156","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T05:37:32Z","timestamp":1787290652000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics identification and functional validation of signal regulatory protein gamma as a 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