{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T08:27:01Z","timestamp":1787128021565,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Although papillary thyroid carcinoma (PTC) is widely considered an immunologically cold tumor, detectable T-cell infiltration can influence disease progression in selected patients. Previous bulk analyses have linked cAMP-responsive element modulator (CREM) expression to a favorable progression-free interval and an inverse correlation with regulatory T-cell infiltration but have not resolved the cellular origin or functional state. In this study, we integrate single-cell RNA-sequencing data from a 23-sample PTC atlas with bulk Cancer Genome Atlas Thyroid Carcinoma (TCGA\u2013THCA) validation. We show that CREM marks a T-cell receptor (TCR)-driven immediate early gene activation state in tumor-infiltrating T cells rather than a cAMP program; this state is consistently and modestly enriched within the FOXP3+ regulatory T-cell compartment, challenging the interpretation that bulk inverse Treg\u2013CREM correlations reflect Treg-intrinsic repression. CREM-high T cells upregulate ANXA1, and permutation-controlled analysis identifies a candidate paracrine axis from CD4\/CD8 T cells to the epithelial epidermal growth factor receptor (EGFR). At the bulk level, CREM expression correlates with reduced proliferation programs and is associated with a prolonged progression-free interval (multivariate HR 0.56, 95% CI 0.31\u20131.00, p = 0.050), with the effect direction preserved after immune and sex adjustment. Genome-wide differential expression and gene-set enrichment in an independent cohort (GSE193581) confirm that CREM-detected T cells are enriched for a TCR-driven immediate early transcriptional program, supporting the reinterpretation of CREM as a marker of TCR-driven IEG activation.<\/jats:p>","DOI":"10.3390\/ijms27167387","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:12:11Z","timestamp":1787069531000},"page":"7387","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CREM Marks TCR-Driven T-Cell Activation and Associates with Favorable Prognosis in Papillary Thyroid Carcinoma: A Single-Cell and Bulk Transcriptomic Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0687-5778","authenticated-orcid":false,"given":"Hao","family":"Ling","sequence":"first","affiliation":[{"name":"Department of Surgery, Klinikum Rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Institute for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhu","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Klinikum Rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7845-5208","authenticated-orcid":false,"given":"Yan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Genetics & Cell Biology, Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Institute for Oncology and Reproduction (GROW), Maastricht University, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1001\/jama.2023.26348","article-title":"Thyroid Cancer: A Review","volume":"331","author":"Boucai","year":"2024","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Forma, A., K\u0142odnicka, K., Paj\u0105k, W., Flieger, J., Teresi\u0144ska, B., Januszewski, J., and Baj, J. 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