*Review* **Poorly Differentiated and Anaplastic Thyroid Cancer: Insights into Genomics, Microenvironment and New Drugs**

**Alessandro Prete 1, Antonio Matrone <sup>1</sup> , Carla Gambale 1, Liborio Torregrossa 2, Elisa Minaldi 1, Cristina Romei 1, Raffaele Ciampi 1, Eleonora Molinaro <sup>1</sup> and Rossella Elisei 1,\***


**Simple Summary:** In the last decades, many researchers produced promising data concerning genetics and tumor microenvironment of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC). They are trying to tear the veil covering these orphan cancers, suggesting new therapeutic weapons as single or combined therapies.

**Abstract:** PDTC and ATC present median overall survival of 6 years and 6 months, respectively. In spite of their rarity, patients with PDTC and ATC represent a significant clinical problem, because of their poor survival and the substantial inefficacy of classical therapies. We reviewed the newest findings about genetic features of PDTC and ATC, from mutations occurring in DNA to alterations in RNA. Therefore, we describe their tumor microenvironments (both immune and not-immune) and the interactions between tumor and neighboring cells. Finally, we recapitulate how this upcoming evidence are changing the treatment of PDTC and ATC.

**Keywords:** anaplastic thyroid cancer; poorly thyroid cancer; genetic landscape; tumor microenvironment; genetically guided therapy
