Suppressed cGAS–STING DNA Sensing Drives Immune Evasion in Anaplastic Thyroid Cancer

Background: Anaplastic thyroid cancer (ATC) is a highly lethal malignancy with poor survival and limited therapeutic options. The mechanisms driving immune evasion in ATC remain poorly understood. The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is a key mediator of innate immune sensing and antitumor immunity. Methods: We investigated the role of cGAS–STING signaling in ATC using three complementary models (i) a genetically engineered mouse model harboring triple mutations in Thrb1 , Trp53 , and Pten (RU3 model); (ii) an orthotopic tumor model derived from Trp53 - and Braf -mutant ATC cells; and (iii) subcutaneous tumor models of Ifnb1 - or Trp53 -expressing ATC cells. Tumor immune microenvironment alterations were assessed using comprehensive molecular approaches, including single-cell RNA sequencing. Results: The models demonstrated marked suppression of cGAS–STING signaling during ATC progression. This suppression was associated with impaired antitumor immunity, characterized by reduced CD8 + T cell infiltration and diminished type I interferon (IFN-I) responses. Restoration of IFNβ1 signaling in ATC cells significantly enhanced CD8 + T cell recruitment and inhibited tumor growth in vivo . These findings indicate that immune evasion in ATC is driven by decreased IFNβ1 production rather than resistance to its downstream effects. Mechanistically, p53 was found to sustain cGAS–STING–IFNβ1-mediated antitumor immunity, and its loss contributed to reduced IFNβ1 expression and immune escape. Conclusions: Impaired DNA sensing via suppression of the cGAS–STING–IFNβ1 axis promotes immune evasion in ATC. Therapeutic strategies aimed at restoring this pathway may enhance antitumor immunity and represent a promising approach for treating this aggressive disease.