Thyroid Gland Anaplastic Carcinoma

Lonafarnib effectively suppresses the malignant progression of anaplastic thyroid carcinoma both in ATC cell lines and in a BALB/c nude mouse xenograft model. The mechanism involves inhibition of Ras farnesylation and the downstream ERK signaling pathway, leading to activation of Caspase-3/PARP-mediated apoptosis and GSDME-mediated pyroptosis.

We confirmed that Regorafenib disrupts this entire axis and, in combination with anti-PD-1 therapy in ATC, overcomes immunosuppression to elicit potent anti-tumor immunity. Our studies revealed the GPI/O-GlcNAcylation/THBS1 signal as a master regulator of myeloid cell crosstalk and established a novel therapeutic strategy for targeting this metabolic checkpoint to potentiate ATC immunotherapy.

Knockdown of NTRK1, which encodes TrkA, reduced cell viability and sensitized ATC cells to paclitaxel. Entrectinib was well tolerated at the administered dose, with no significant changes in body weight and serum biochemical markers. Collectively, these findings identify TrkA as a potential therapeutic target in ATC and support further investigation of entrectinib-based combination strategies to improve ATC treatment outcomes.

Importantly, the treatment exhibited favorable biocompatibility and mitigated DOX-induced cardiotoxicity. Collectively, this PTT-chemotherapy combination enhances antitumor efficacy through multiple mechanisms while reducing systemic toxicity, representing a promising strategy with translational potential for ATC treatment.

Initial in vitro validation in a single RAIR-high/ATC-like thyroid cancer model provided proof-of-concept support for these predictions, with sorafenib showing dose-dependent cytotoxicity and suppression of RAF-MAPK signalling. A module-based RAIR signature captures a disease-focused component of a broader RAIR-ATC axis, transfers to cell-line models and can be embedded into an interpretable multimodal framework for drug-response prediction and targeted drug-class prioritisation, prioritising VEGFR/KDR and RAF/BRAF inhibitor classes as candidates for further translational evaluation in RAIR-like thyroid models.

The cytotoxic effects of three MAPK pathway inhibitors (selumetinib, vemurafenib, dabrafenib) were assessed in ATC cell lines and xenograft models via viability assays and 18F-FDG PET/CT. Furthermore, MAPK pathway inhibitors increased radioiodine uptake in ATC cells. The MAPK pathway inhibitors enhance NIS function through two mechanisms: upregulation of NIS expression and increased ARF4-mediated NIS membrane transport.

Accordingly, this review provides an overview of both classical knowledge and recent molecular findings related to ATC and integrates these insights to present an updated framework for differential diagnosis and diagnostic approach. In addition, we discuss recent advances in immunohistochemistry, including mutation-specific antibodies and novel diagnostic markers, and highlight their relevance in the context of contemporary diagnostic pathology and evolving therapeutic strategies.

HN1 forms complex with transcription factor CCAAT/enhancer binding protein beta (CEBPB) to prevent CEBPB from ubiquitination and degradation, thereby promoting CCL2 transcription. In summary, our findings demonstrate HN1/CCL2/VSIG4 axis is essential for fostering immunosuppressive microenvironment in ATC, shed light on potential targets concerning cancer cell-TAMs crosstalk.

ATC microenvironment is rich in immunosuppressive MDSCs. These findings support MDSC-focused immunomodulation as a promising adjunct therapy in ATC.

However, significant challenges remain, including the high cost of multi-omics integration and the lack of standardized protocols for clinical implementation. We conclude by envisioning a future integrated with multimodal AI models, patient-derived organoids (PDOs), and metabolic reprogramming markers, aiming to provide a holistic framework for the "early screening-precise diagnosis-tailored therapy-dynamic monitoring" continuum in thyroid oncology.

Molecular testing was associated with improved survival in ATC, likely driven by the identification of actionable alterations with effective targeted therapies. Local management is key in all stages. Our findings also support immunotherapy, tyrosine kinase inhibitors and their combinations as key therapeutic options.

We have recently demonstrated that a RAC1 mutation (RAC1 P34R) can induce the formation of PGCCs in aggressive thyroid cancer cells from a patient undergoing dabrafenib treatment, leading to resistance to therapy...By targeting RAC1's integrative functions, researchers may unlock new avenues for preventing PGCC-mediated recurrence and metastasis, offering a promising strategy to improve long-term outcomes in cancer treatment. This review outlines the diverse functions of RAC1 that may contribute to both the formation and sustained maintenance of PGCCs across various tumor types.