Innovative immunotherapeutic strategies for thyroid cancer: challenges and opportunities

Thyroid cancer is the seventh most prevalent cancer worldwide, with a growing incidence and mortality rate. This malignancy encompasses distinct subtypes with diverse biological behaviors, clinical outcomes, and therapeutic vulnerabilities. While most thyroid cancer cases are associated with a favorable prognosis and respond well to conventional therapies, such as surgery and radioactive iodine therapy, advanced, recurrent, or dedifferentiated subtypes have a bad prognosis and limited therapeutic options, necessitating the development of more efficacious therapeutic strategies. Despite the remarkable progress of immunotherapeutic strategies across multiple malignancies, the translation of these approaches into thyroid cancer has been comparatively slow and inconsistent. Except for immune checkpoint inhibitor (ICI) therapy, other types of immunotherapy in thyroid cancer have not yet been advanced beyond early-stage clinical trials. This is attributed to the intrinsic nature of thyroid tumors, which are widely considered cold tumors with low mutational burden and a high immunosuppressive tumor microenvironment (TME). Nonetheless, recent studies indicate that by understanding the immunobiology of different subtypes of thyroid cancers, immunotherapeutic strategies can be adapted to their unique molecular, cellular, and microenvironmental characteristics, thereby improving therapeutic efficacy. This review aims to discuss the progress and pitfalls of various immunotherapy approaches for thyroid cancer, including ICI therapies, adoptive cell therapies (CAR-T cell, TCR-T cell, and TIL therapy), oncolytic virotherapy, and macrophage/myeloid-modulating immunotherapies. A deeper understanding of subtype-specific immunobiology and precise tailoring of immunotherapeutic interventions may ultimately enable more effective and durable clinical responses for patients with advanced thyroid cancer.