**5. Conclusions**

The study of several molecular pathways and the tumor microenvironment involved in cancer development has recently guided the scientific community's effort to clarify tumor behavior. Indeed, proliferation pathways, cell cycle control pathways, and the processes of angiogenesis have been largely evaluated, providing new tools useful in screening, diagnosis, and follow-up of thyroid cancer and allowing the identification of mediators that may be potential targets for new anticancer treatments.

VEGF and its receptors appear to be the major players in the angiogenesis process of thyroid tumors. There have been numerous efforts toward understanding the signaling mechanisms driven by BRAFV600E mutation and loss of Pten as a contribution to the angiogenic process in the thyroid tumor microenvironment. For these reasons, antiangiogenic therapy is used in all histological subtypes of thyroid cancer. In addition, to date, a number of inhibitors of the RAS, RAF and MEK pathways and other types of molecular target therapy have been shown to be effective in vitro and require clinical confirmation.

The tumor microenvironment presents numerous barriers that prevent access to chemotherapies, not only rendering them often ineffective but also potentially increasing the tumor cells' aggressiveness.

Prognostic indicators are based on dynamic interactions between multiple types of cells, especially those with immune functions belonging to the tumor microenvironment.

Further studies are needed to increase knowledge of the tumor microenvironment and to evaluate its changes and remodeling as thyroid cancer progresses.

Additionally, other studies should aim to determine the role of the immune system in thyroid cancer.

**Author Contributions:** Conceptualization, A.M., L.I.S., A.P., R.R. and M.T.; writing—original draft preparation, A.M., L.I.S. and A.P.; writing—review and editing, A.G., A.V., R.R. and M.T.; methodology, A.M., L.I.S., A.P., A.M., G.D.M., F.P.P., R.R. and M.T.; resources, A.M., G.D.M. and F.P.P.; validation, A.G., A.V., R.R. and M.T.; supervision, A.G., A.V., R.R. and M.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
