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.