PPP2R2A insufficiency enhances PD-L1 immune checkpoint blockade efficacy in lung cancer through cGAS-STING activation.

ABSTRACT: PP2A B55α, a regulatory subunit of protein phosphatase 2 (PP2A), is underexpressed in greater than 40% of non-small cell lung cancer (NSCLC) cases due to loss of heterozygosity of PPP2R2A, the gene encoding this protein. Given that low PPP2R2A expression correlates with poor prognosis, treating PPP2R2A-deficient NSCLC represents an unmet medical need. Here, we show that PPP2R2A knockdown or its heterozygosity (PPP2R2A+/-) increases cytosolic DNA, leading to cGAS-STING-type I IFN pathway activation. PPP2R2A deficiency results in elevated expression of immune checkpoint protein PD-L1 via GSK-3β- and STING-dependent mechanisms. PPP2R2A+/- cancer cells have enhanced sensitivity to PD-L1 blockade in a mouse model of lung cancer due to modulation of the tumor immune microenvironment, resulting i

SUBMITTER: Qiu Z 

PROVIDER: S-EPMC12904717 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature