Turning tumor microenvironmental foes to friends: A new opportunity for thyroid cancer therapy and redifferentiation.

Cancer cells engage in dynamic crosstalk with their microenvironment (TME), critically influencing tumor progression, metastasis, immune evasion, and therapeutic resistance. Thyroid cancer (TC) exhibits characteristic tumor heterogeneity, together with secreted factors (cytokines, chemokines, extracellular vesicles) and the extracellular matrix, these elements constitute the TME. In addition, TC-TME interactions drive key pathological processes including differentiation status across histological subtypes-from differentiated (DTC) to aggressive variants(poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC)). A hallmark of malignancy, metabolic reprogramming not only fuels uncontrolled proliferation but also actively remodels the TME through mechanisms including immune modulation, angiogenesis regulation, and stromal reprogramming. At the same time, immunotherapy represents a promising therapeutic frontier for treatment-refractory cases such as radioiodine-resistant DTC (RR-DTC), PDTC, and ATC. Emerging evidence reveals distinct mutational signatures that correlate with TME remodeling, suggesting potential diagnostic and prognostic biomarkers. While current redifferentiation approaches primarily target cancer cells with limited success, novel strategies focusing on TME modulation-particularly targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and tumor-associated mast cells (TAMCs)-show therapeutic potential. Deciphering these intricate metabolic adaptations and their bidirectional interactions with the TME represents a pivotal opportunity for developing precision therapies and enhancing treatment efficacy in the clinical oncology of TC. This review synthesizes current knowledge on TME-directed therapies in TC and highlights the urgent need to elucidate metabolic reprogramming and other factors within the TME to develop innovative treatment paradigms targeting both cancer cells and TC-associated immune cells.