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

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.