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

作者：Zhaojun Qiu, No Joon Song, Anqi Li, Deepika Singh, Chandra Bhushan Prasad, Chunhong Yan, David P. Carbone, Qi-En Wang, Xiaoli Zhang, Zihai Li, Junran Zhang · 发表于：Journal of Clinical Investigation · 年份：2025 · DOI：10.1172/jci193354 · 被引用次数：6 · 研究领域：interferon and immune responses、Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis

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 in increased NK cells and reduced infiltration and function of Tregs. Consequently, PD-L1 antibody treatment increases CD8+ T infiltration and activity, especially in tumors with PPP2R2A heterozygosity. Furthermore, systemic or Treg-specific IFNAR1 blockade reduces the efficacy of PD-L1 blockade in PPP2R2A+/- tumors. Patients with NSCLC with a low PPP2R2A/PD-L1 ratio respond better to immune checkpoint blockade (ICB). These findings underscore the therapeutic potential of ICB in treating PPP2R2A-deficient NSCLC and suggest that PPP2R2A deficiency could serve as a biomarker for guiding ICB-based therapies.