Tumor microenvironment-guided targeted and immunotherapy in anaplastic thyroid cancer: a literature review from preclinical models to clinical translation.

Abstract

<h4>Background and objective</h4>Anaplastic thyroid cancer (ATC) is among the most aggressive human malignancies, with a median survival of 3-6 months. The tumor microenvironment (TME) drives progression and therapeutic resistance. We provide a narrative literature review integrating preclinical and clinical advances in TME-guided targeted therapy and immunotherapy.<h4>Methods</h4>We systematically searched PubMed and Web of Science Core Collection for English-language studies on ATC TME, targeted therapy, and immunotherapy (January 2020-August 2025). Search strategies combined Medical Subject Headings (MeSH) terms and free-text keywords. We included preclinical and clinical original research while excluding reviews, editorials, and conference abstracts.<h4>Key content and findings</h4>We synthesized 129 studies: 69 preclinical targeted-therapy, 19 clinical targeted-therapy, 13 preclinical immunotherapy, 6 clinical immunotherapy, and 22 clinical combination-therapy studies. ATC features a paradoxical TME with concurrent immune activation and suppression. Tertiary lymphoid structures and C-X-C motif chemokine ligand 13 (CXCL13)⁺ T cells emerge as immunotherapy biomarkers. In <i>BRAF</i>-mutant disease, BRAF/mitogen-activated protein kinase (MEK) inhibitors plus immune checkpoint inhibitors extended median survival from 9 to 17 months, with neoadjuvant reporting reaching 63 months. For non-targetable mutations, anti-angiogenic tyrosine kinase inhibitors (TKIs) plus immunotherapy achieved 66% complete response rates. TME-guided neoadjuvant combinations converted 38.9% of unresectable cases to resectable disease.<h4>Conclusions</h4>This review provides clinicians with decision-making frameworks for TME-based treatment selection and identifies future research directions. Future directions include TME-stratified trials, biomarker standardization, and development of streamlined treatment algorithms to translate these advances into routine practice.