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To address these gaps, we examined six postnatal (one male and five female) and two prenatal (both female) SCTs by single nuclei RNA-seq and spatial transcriptomics. We identified five broad cellular lineages in SCTs: stroma, epithelia, endothelia, neuroectoderm, and immune. The transcriptomes and lineage compositions showed significant heterogeneity, which offer a framework for future molecular stratification. SCTs are thought to originate from and be propagated by pluripotent cells, notably however, we did not detect these populations. Among female tumors, a subset of cells exhibited biallelic expression of X-linked genes, consistent with X-inactivation failure or reactivation of the once inactivated X-chromosome. These biallelic cells were enriched for developmental and neuronal programs, whereas cells with single-allelic X-chromosome preferentially expressed immune-related genes. Biallelic X-chromosome activation, which can occur only in female cells, may result in transcriptomic features that favor survival of tumor cells, contributing to the sex bias of SCTs. Our findings reveal a link between X-chromosome inactivation and SCT cell identity, suggesting that X-dosage dysregulation may influence SCT heterogeneity and immune landscape.<\/jats:p>","DOI":"10.1101\/2025.07.21.665156","type":"posted-content","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T22:55:14Z","timestamp":1753397714000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrated single-nuclei and spatial transcriptomic profiling of human sacrococcygeal teratomas reveals heterogeneity in cellular composition and X-chromosome inactivation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6837-7678","authenticated-orcid":false,"given":"Ernesto J.","family":"Rojas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9633-3541","authenticated-orcid":false,"given":"Krinio","family":"Giannikou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6996-0833","authenticated-orcid":false,"given":"Benjamin J.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6324-6858","authenticated-orcid":false,"given":"Soo-Jin","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1265-624X","authenticated-orcid":false,"given":"Marco A.","family":"Cordero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deion","family":"Pena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Vu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3358-1193","authenticated-orcid":false,"given":"Aditya","family":"Bagrodia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-0730","authenticated-orcid":false,"given":"S. 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