Low baseline cGAS expression is associated with longer progression-free survival in patients with pleural mesothelioma.

INTRODUCTION: The cyclic GMP-AMP synthase (cGAS)/STING pathway, a central DNA-sensing mechanism, is known to activate anti-tumor immune response but may also promote tumor progression when chronically activated. Given the role of asbestos-induced chronic inflammation in pleural mesothelioma (PM), we investigated cGAS/STING expression and its association with treatment outcomes.

METHODS: We analyzed tissue microarrays from 190 PM patients using multiparameter immunofluorescence single-cell imaging. cGAS and STING expression were quantified in Calretinin+ tumor cells, Calretinin-CD8-DC-LAMP- cells, and CD8+ cells before and after chemotherapy. Associations with treatment response and survival were assessed.

RESULTS: In matched pre- and post-treatment samples, total cGAS+ cell frequency increased after chemotherapy, as did cGAS+ frequencies in Calretinin+ tumor cells, Calretinin-CD8-DC-LAMP- cells, and CD8+ cells after FDR correction, whereas STING+ cell frequency did not differ. Within the progressive-disease subgroup, significant paired increases were retained for total cGAS+ cells and Calretinin-CD8-DC-LAMP- cells. However, the magnitude of change did not differ significantly among patients with partial response, stable disease, or progressive disease. Low baseline total cGAS+ frequency and cGAS+ frequency in Calretinin-CD8-DC-LAMP- cells were associated with longer progression-free survival. In an exploratory analysis of the TCGA PM cohort, higher CGAS/MB21D1 transcript expression was associated with shorter overall survival in continuous Cox regression, whereas STING1 transcript expression was not significantly associated with overall survival when analyzed as a continuous variable.

CONCLUSIONS: Low baseline cGAS+ frequency, particularly in the Calretinin-CD8-DC-LAMP- compartment, was associated with longer progression-free survival in PM. These findings support further evaluation of cGAS as a candidate prognostic biomarker but do not establish cGAS as a predictor of chemotherapy response or as a causal driver of treatment resistance.