Abstract 6993: Targeting PDE4A ablates an immune checkpoint and unleashes STING-Driven anti-tumor immunity

Abstract Dysregulation of the cGAS-STING pathway is a common mechanism of immune evasion. Here, we identify phosphodiesterase 4A (PDE4A) as a pivotal suppressor of this pathway in tumor cells. High PDE4A expression dampens cGAS-STING signaling and type I interferon production, resulting in impaired infiltration of cytotoxic CD8+ T cells into the tumor microenvironment and accelerated metastasis. Strikingly, both genetic knockdown of PDE4A and its pharmacological inhibition with roflumilast reversed this immune-suppressive phenotype, potently enhanced CD8+ T cell infiltration, and suppressed metastatic progression. Our findings unveil PDE4A as a novel therapeutic target to reactivate anti-tumor immunity and combat metastasis, nominating PDE4A inhibition, particularly with the clinically available agent roflumilast, as a promising immunotherapeutic strategy. Citation Format: Yuting Bai, Kejia Xu, Huimin Liu, Haojie Chen, Yi Shi, Rong Xiang. Targeting PDE4A ablates an immune checkpoint and unleashes STING-Driven anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6993.