Cyclic GMP-AMP Synthase Expression in Hepatocellular Carcinoma: A Double-Edged Biomarker for Prognosis and Immunotherapy Response.

Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality. Although atezolizumab plus bevacizumab (ATZ/BEV) is the standard therapy, only a subset of patients achieves durable responses. Cyclic GMP-AMP synthase (cGAS) regulates innate immunity, but its clinical role in HCC is unclear. Patients with primary HCC were retrospectively analyzed and divided into cohort 1 (353 patients who underwent hepatectomy without prior therapy) and cohort 2 (42 patients who received ATZ/BEV after recurrence). In cohort 1, cGAS expression was quantified by immunohistochemistry and analyzed for correlations with clinicopathological features, disease-free survival (DFS), overall survival (OS), and independent prognostic factors. In cohort 2, cGAS was assessed for associations with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). In cohort 1, 25.4% of patients had high cGAS expression (immunohistochemistry score ≥ 3). Although cGAS expression was unrelated to clinicopathological factors, it was associated with shorter DFS (2.37 versus 3.72 years; p = 0.019) and OS (6.19 years versus not reached; p = 0.002). Multivariate analysis identified cGAS positivity as an independent predictor of poor prognosis. Conversely, in cohort 2, high cGAS expression correlated with longer PFS after ATZ/BEV (12.6 versus 6.5 months; p = 0.020) and higher ORR (43.8% versus 11.5%; p = 0.0173) and DCR (93.8% versus 65.4%; p = 0.0361). cGAS functions as a dual biomarker, predicting poor prognosis after hepatectomy but favorable response to immunotherapy. These findings underscore the clinical relevance of cGAS and its potential to guide personalized HCC treatment.