**3. Tumor Microenvironment**

Tumor microenvironment (TME) is the dynamic milieu that harbors tumor cells [94]. It comprises blood vessels, extracellular matrix (ECM), non-neoplastic cells, and signaling molecules [95]. Neoplastic cells interact with other TME members in order to regulate self-growth, invasiveness and resistance to therapy [94]. In thyroid, many reports showed that TME may promote tumor growth, metastatic power, and resistance to therapy, both in differentiated and anaplastic thyroid cancer [96–98].

In TME we should distinguish not immune and immune related cells. Among the former, cancer associated fibroblasts play a relevant role in both ATC and PDTC [99,100]. In ATC, tumor cells present paracrine communication with fibroblast: ATC cells activate fibroblasts by reprogramming their metabolism, phenotype and secretome, and then activated fibroblasts reinforce thyroid cancer progression, by enhancing tumor invasion and proliferation [100]. Likewise, interactions between PDTC cells and cancer associated fibroblasts may potentiate tumor progression, by collagen remodeling [99]. Analog interplays have been recently demonstrated between ATC and endothelial cells, partially rescued by sorafenib [94].

Giannini et al. provided significant evidence about immune TME in ATC and PDTC [101]. ATC TME was enriched of tumor infiltrating leukocytes (both macrophage and lymphocytes) and characterized by hot or altered–immunosuppressed phenotype, since a relevant part of CD8+ lymphocytes presented exhausted features. Accordingly, Caillou et al. showed that tumor-associated macrophages build up a dense network in whom cancer cells reside [102,103] and their presence is associated with a worse prognosis in ATC [104]. Cameselle-García and colleagues elucidated that ATC tumors are enriched of tumor infiltrating lymphocytes (mainly CD8+ cytotoxic T cells), which mainly reside in the interface between tumor ant thyroid tissue [105]. Otherwise, PDTC harbored less tumor infiltrating leukocytes compared to ATC, and presented a cold immune contexture in 65% of cases [101]. In these immune contexts, PD/PD-L1 pathway (programmed cell death protein-1/programmed cell death ligand-1) plays a crucial role in ATC and less frequently also in PDTC [97,105,106]. If in physiologic conditions, PD/PD-L1 pathway regulates T cell immune suppression, in neoplastic milieu it is exploited by cancer cells in order to avoid immune attack, by inducing T-cell exhaustion [107]. In ATC, PD/PD-L1 proteins expression was shown to be regulated by BRAF mutation and is was associated to a worst prognosis [106,108]. Accordingly, Brauner et al. demonstrated that dual inhibition of BRAF and PD/PD-L1 pathways induced a powerful shrinkage of ATC tumor in orthotopic immune-competent mouse model [108].
