{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T01:51:32Z","timestamp":1785030692261,"version":"3.55.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"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:p>Thyroid cancer (TC) is now among the fastest-growing solid tumours, yet therapeutic gains remain limited for poorly differentiated, anaplastic and medullary variants whose median survivals are measured in months. Once guided chiefly by histology and single-gene assays, immunotherapy is being reshaped by single-cell profiling, which exposes the cellular mosaics that arbitrate response and resistance. Dissection of more than 150\u2013000 tumour- and immune-cell transcriptomes has uncovered follicular-like, partial EMT-like and dedifferentiated thyrocyte states embedded within \u2018hot\u2019 (CD8<jats:sup>hi<\/jats:sup> IFN-\u03b3<jats:sup>hi<\/jats:sup>), \u2018cold\u2019 (CD8<jats:sup>lo<\/jats:sup>) and \u2018excluded\u2019 (stroma-walled) immune niches; these phenotypes correlate with PD-1\/LAG-3 expression, macrophage polarisation and radio-iodine refractoriness. Functional studies reveal that SPP1\u2013CD44 and GAS6\u2013AXL crosstalk licenses epithelial\u2013mesenchymal transition while VSIG4<jats:sup>+<\/jats:sup> macrophages blunt cytotoxic T-cell activity, collectively undermining checkpoint blockade. Spatial transcriptomics corroborates these insights, mapping PD-L1-high tumour islets millimetres from CXCL13-rich tertiary lymphoid structures, whereas CITE-seq quantifies actionable checkpoints and cytokine receptors across patient biopsies. Emerging therapeutics mirror this granular knowledge: combinatorial PD-1 + LAG-3 inhibition, CSF-1R-directed macrophage re-programming and TSH-receptor-targeted CAR-T cells are advancing through early-phase trials, while ex-vivo single-cell pharmacotyping aligns drug cocktails with an individual\u2019s tumour ecosystem. Early lenvatinib-pembrolizumab or selpercatinib-nivolumab trials show ~40% ORR but grade-3 hypertension &amp;gt;60%, prompting staggered-start designs. These advances sharpen pathogenetic resolution, refine patient selection and accelerate translational pipeline design. By integrating single-cell biology, immunology and endocrine oncology, this review identifies diagnostic blind spots, spotlights drug-repurposing opportunities and charts a roadmap toward personalised immunotherapeutic strategies capable of improving outcomes across the diverse spectrum of thyroid cancer.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1651088","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:29:25Z","timestamp":1756704565000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Personalised immunotherapy strategies informed by single cell profiling in thyroid cancer: a mini 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