Simple SummaryThe majority of DTCs exhibit a favorable prognosis, while a minority of subtypes are fatal, thus highlighting the need for effective treatments for aggressive TCs. Molecular studies of this aggressive tumor have received increasing attention. Recent studies have revealed a crosstalk between immune cells and TC in TME, emphasizing the role of chemo-kinesin/cytokines. Immunotherapy has emerged as a promising avenue to combat aggressive TC, with studies highlighting the mechanisms underlying TC progression, identifying immune cells as prognostic markers and therapeutic targets, and recommending immunotherapy-based interventions. However, the development of highly specific and safe targeted drugs for TC remains a major challenge and requires a more detailed understanding of the molecular underpinnings and immunotherapy.AbstractThyroid cancer (TC) is the most common malignancy in the endocrine system. Although most TC can achieve a desirable prognosis, some refractory thyroid carcinomas, including radioiodine-refractory differentiated thyroid cancer, as well as anaplastic thyroid carcinoma, face a myriad of difficulties in clinical treatment. These types of tumors contribute to the majority of TC deaths due to limited initial therapy, recurrence, and metastasis of the tumor and tumor resistance to current clinically targeted drugs, which ultimately lead to treatment failure. At present, a growing number of studies have demonstrated crosstalk between TC and tumor-associated immune cells, which affects tumor deterioration and metastasis through distinct signal transduction or receptor activation. Current immunotherapy focuses primarily on cutting off the interaction between tumor cells and immune cells. Since the advent of immunotherapy, scholars have discovered targets for TC immunotherapy, which also provides new strategies for TC treatment. This review methodically and intensively summarizes the current understanding and mechanism of the crosstalk between distinct types of TC and immune cells, as well as potential immunotherapy strategies and clinical research results in the area of the tumor immune microenvironment. We aim to explore the current research advances to formulate better individualized treatment strategies for TC patients and to provide clues and references for the study of potential immune checkpoints and the development of immunotherapy technologies.