Radioiodine-induced cGAS-STING signaling and antitumor immunity in thyroid cancer

Abstract

Radioiodine (RAI) is a cornerstone of treatment for differentiated thyroid cancer (DTC), yet the immunological consequences of RAI-induced DNA damage remain poorly understood. Here, we examine cGAS–STING signaling as a potential mechanistic link between RAI-induced genotoxic stress and antitumor immunity. RAI delivers prolonged, thyroid-selective radiation to iodine-avid tumors, providing a plausible source of extranuclear DNA capable of engaging innate DNA sensing. We propose that transient RAI-associated cGAS–STING activation in DTC may favor IRF3–type I interferon-dependent immune priming, whereas persistent genomic stress in RAI-refractory anaplastic and poorly differentiated thyroid cancers (ATC/PDTC) may shift pathway output toward NF-κB-dominated, myeloid-suppressive programs. This acute-versus-chronic framework suggests that cGAS–STING dynamics could help define a therapeutic window for sequencing RAI with immune checkpoint blockade, while controlled STING activation may provide an alternative strategy for iodine-refractory disease. Direct evidence for RAI-induced cGAS–STING activation in thyroid tumors remains lacking, highlighting the need to define pathway kinetics across thyroid cancer subtypes and determine whether thyroid-specific endocrine signaling, including TSH–TSHR signaling, further modulates innate DNA sensing.