Anaplastic thyroid carcinoma makes up only about two percent of thyroid cancers, yet causes more than half of thyroid-cancer deaths. This review asks whether targeted drugs, immunotherapy, or their combination can change that outlook. Anaplastic thyroid carcinoma is a rare and aggressive form of thyroid carcinoma, and there are currently no effective treatments for this condition.

Targeted therapy and immunotherapy have made significant progress in ATC treatment, while immunotherapy is still in the experimental stage and is considered a potential therapy. The review also explores whether combining immunotherapy with targeted therapy, radiotherapy, or chemotherapy could enhance treatment effects.

Anaplastic thyroid carcinoma accounts for only approximately two percent of thyroid carcinomas, but contributes to more than fifty percent of all thyroid carcinoma mortality. According to American Thyroid Association guidelines, conventional treatment includes surgery, radiotherapy, and chemotherapy.

The review examines all clinical studies on targeted therapy and immunotherapy for anaplastic thyroid carcinoma, looking for the best ways to combine these treatments. It also connects upstream receptor tyrosine kinases and genetic alterations to targeted drugs, including vemurafenib, dabrafenib, trametinib, lenvatinib, and everolimus.

The figure matters because it shows how therapies are positioned within pathways driving angiogenesis, proliferation, and tumorigenesis. The MAPK signaling pathway plays an important role in the occurrence and development of anaplastic thyroid carcinoma.

After growth factors bind to tyrosine kinase receptors, signaling activates RAS, then BRAF, MEK, and ERK; ERK enters the nucleus and increases transcription factors linked to cell proliferation and cell survival. Tyrosine kinase inhibitors can act against tumors by inhibiting tumor-cell repair, blocking cell division in the G one phase, inducing and maintaining apoptosis, and inhibiting angiogenesis.

Across some phase one and phase two clinical trials of tyrosine kinase inhibitor monotherapy for anaplastic thyroid carcinoma, objective remission occurred in zero to twenty-five percent of patients. Overall, these tyrosine kinase inhibitors showed moderate single-agent activity in anaplastic thyroid carcinoma.

The review says that small patient numbers may contribute to poor responses in some trials, supporting further study in a multi-institutional environment. Tumor diversity and intertwined regulatory mechanisms create challenges for targeted therapies, but mutations in different targets also create possibilities for combining targeted drugs.

For BRAF inhibitors, resistance can involve increased receptor tyrosine kinase expression, upstream mutations, downstream MAPK changes, parallel pathways, BRAF amplification, and alternative splicing. In one study, combining the MEK inhibitor PD0325901 with PLX4720 inhibited anaplastic thyroid carcinoma cell growth better than PLX4720 alone, while trametinib plus pazopanib produced synergistic inhibition in anaplastic thyroid cancer cell lines.

In a phase two study of locally advanced or metastatic BRAF V600 mutant anaplastic thyroid carcinoma, fifteen of sixteen sequenced patients had BRAF mutations, and eleven patients were in remission. Dabrafenib plus trametinib showed strong clinical activity against BRAF V600E mutant anaplastic thyroid carcinoma and was approved by the FDA for BRAF-positive disease.

A separate phase one study is evaluating dabrafenib, trametinib, and intensity-modulated radiation therapy in six patients, with completion expected in April twenty twenty-five. Table one summarizes three ongoing clinical trials of targeted therapy for anaplastic thyroid cancer.

It lists MLN0128, sorafenib, and the combination of dabrafenib and trametinib, along with each trial’s phase, recruitment status, treatment focus, estimated enrollment, and primary completion date. The table matters because it illustrates how clinical studies are testing different strategies, including therapy for metastatic disease, preoperative tumor reduction, and combination treatment with radiation in BRAF-mutated cancer.

Targeted therapeutic agents can achieve potential therapeutic effects in anaplastic thyroid carcinoma, but results for most targeted therapies have been unsatisfactory. Clinical trials are examining the appropriate timing and sequence of targeted therapy, and may provide more comprehensive conclusions about targeted drugs in anaplastic thyroid carcinoma.

Cancer immunotherapy induces, enhances, or inhibits specific immune responses and involves overcoming immune-suppressive signaling, initiating and differentiating T cells, and enhancing tumor-associated antigen presentation. For anaplastic thyroid carcinoma, the review focuses on immune checkpoints, adoptive cell therapy, and oncolytic viruses.

Figure two maps immune-checkpoint and co-stimulatory interactions between a T cell and a cancer cell, while also showing contacts with regulatory T cells, tumor-associated macrophages, and dendritic cells. It highlights pathways including T-cell receptor and MHC class two recognition, inhibitory PD-one and PD-L-one signaling, and the CTLA-four and CD28 interactions with CD80 and CD86.

The figure matters because these competing signals help determine immune activation, suppression, and tumor immune escape, while the authors caution that the displayed ligand and receptor expression is not exhaustive. Spartalizumab is a humanized monoclonal antibody targeting PD-1 on human immune cells, with immune checkpoint inhibition and anti-tumor activity.

In a phase two trial, patients with locally advanced or metastatic anaplastic thyroid carcinoma received four hundred milligrams intravenously every four weeks, and the overall remission rate was nineteen percent. That remission rate included three complete remissions and five partial remissions, supporting spartalizumab's efficacy in anaplastic thyroid carcinoma.

Table two catalogs four clinical trials testing immunotherapy for anaplastic thyroid cancer, including three studies of PD-one antagonists and one combining nivolumab with the CTLA-four antagonist ipilimumab. The trials include HX008, pembrolizumab, PDR001, and nivolumab, with statuses ranging from not yet recruiting to completed or active, not recruiting.

This matters because it shows how checkpoint inhibition is being evaluated across metastatic or locally advanced ATC, while the paper notes that response may also depend on CD8-positive tumor-infiltrating lymphocytes and tumor-antigen recognition. For patients with anaplastic thyroid carcinoma, pembrolizumab combined with lenvatinib effectively delayed disease progression, with a median progression-free survival of sixteen point five months.

However, half of the patients experienced adverse effects, showing the tradeoff that accompanies this combination. A study is evaluating whether adding cemiplimab to standard dabrafenib and trametinib can be effective for anaplastic thyroid carcinoma. In the experimental groups, immunotherapy combined with targeted therapy was more effective than either immunotherapy alone or targeted therapy alone.

The review also stresses that few clinical experiments have examined this combination, so further research is needed. Table Three catalogs clinical trials testing combination strategies for anaplastic thyroid cancer, including immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy.

The listed studies span Phase One, Phase Two, and I/II designs, with statuses ranging from recruiting and active—not recruiting to completed or suspended. This matters because the authors note that, although combination approaches appear more effective in experimental groups, relatively few clinical studies have evaluated them, underscoring the need for further research.

Anaplastic thyroid carcinoma is a rare, aggressive thyroid cancer with the worst prognosis, and traditional treatments include surgery, radiotherapy, and conventional chemotherapies. Those traditional treatments are insufficient, while targeted therapy may improve therapeutic effects and quality of life but has greater adverse effects.

Because monotherapy for anaplastic thyroid carcinoma was not satisfactory, researchers considered multi-drug combination therapy strategies. Toxicity is the biggest limitation of combination immunotherapy and is more serious when PD-1 or PD-L1 targeted drugs are combined with CTLA-4 inhibitory monoclonal antibodies.

Combination regimens also require attention to treatment sequence and timing, while predictive biomarkers are urgently needed to guide precise immunotherapy and new combination strategies. The review points toward combination treatment: targeted therapy has demonstrated activity, immunotherapy remains experimental but promising, and future progress depends on controlling resistance, toxicity, and treatment timing with better biomarkers.