Therapeutic treatments targeting communication between angiogenic and immune microenvironments in thyroid cancers

Thyroid cancer treatment has recently been revolutionized by the introduction of specific targeted therapies (e.g. BRAF^V600E or highly selective RET inhibitors), anti-angiogenic agents (e.g. tyrosine kinase inhibitors (TKIs)) and immune checkpoint inhibitors, which significantly ameliorate outcomes in selected groups of thyroid cancer patients. Targeted and anti-angiogenic treatments are characterized by transient and partial efficacy, due to primary or secondary tumor resistance mechanisms, and toxicity profile. Immune therapy-based approaches are producing preliminary results. Herein, we review and prospectively discuss the immune microenvironment in non-medullary and medullary thyroid cancers and its interplays with the angiogenic microenvironment (endothelial cells and pericytes). In addition, we discuss how these interactions might be targeted using combined therapies. Furthermore, we will review chimeric antigen receptor (CAR) T cells treatment that potentially may ensure a more durable and effective response in advanced thyroid cancers. In sum, angiogenic and immune microenvironments show functional connectivity in TCs. Therapies with anti-angiogenic and immune checkpoint inhibitors combined with specific targeted therapy inhibitors with a tolerable toxicity profile may overcome drug resistance and provide better clinical outcomes than single agents.