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Our study revealed a negative correlation between exhausted CD8<jats:sup>+<\/jats:sup> T lymphocytes and prognosis in thyroid carcinoma (THCA). Consensus clustering divided patients into two subgroups of exhaustion with different prognoses, as defined by marker genes of exhausted CD8<jats:sup>+<\/jats:sup> T cells. Subsequently, we constructed an eight-gene prognostic signature, and developed a risk score named the exhaustion-related gene score (ERGS) to forecast both prognosis and immunotherapy response in THCA. Bulk RNA sequencing analysis revealed a higher prevalence of M2 macrophages, indicative of an immunosuppressive tumor microenvironment (TME), in the high-ERGS group. Single-cell RNA sequencing showed that SPP1<jats:sup>+<\/jats:sup> macrophages and CD14<jats:sup>+<\/jats:sup> monocytes infiltrations were positively associated with higher ERGS. Functionally, it was determined that SPP1<jats:sup>+<\/jats:sup> macrophages exert an immunosuppressive role, while CD14<jats:sup>+<\/jats:sup> monocytes were implicated in promoting tumor progression and angiogenesis. Analysis of cell\u2013cell interactions between SPP1<jats:sup>+<\/jats:sup> macrophages and T cells highlighted the activation of the SPP1-CD44 and MIF-CD74 axes, both of which could foster an immunosuppressive TME. Therapeutic strategies that target SPP1<jats:sup>+<\/jats:sup> macrophages, CD14<jats:sup>+<\/jats:sup> monocytes, and the SPP1-CD44 and MIF-CD74 axes may potentially improve the prognosis and amplify the immunotherapy response in THCA patients.<\/jats:p>","DOI":"10.1038\/s41598-024-58419-7","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T08:02:05Z","timestamp":1712736125000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Novel T cell exhaustion gene signature to predict prognosis and immunotherapy response in thyroid carcinoma from integrated RNA-sequencing analysis"],"prefix":"10.1038","volume":"14","author":[{"given":"Yang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangting","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahu","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixi","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"key":"58419_CR1","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/S2213-8587(22)00035-3","volume":"10","author":"M Pizzato","year":"2022","unstructured":"Pizzato, M. et al. 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