PP2Ac 缺失通过激活胶质母细胞瘤中的 STING-I 型干扰素信号通路增强肿瘤免疫原性

UNLABELLED: Glioblastoma (GBM) is an immunologically "cold" tumor that does not respond to current immunotherapy.

Here, we demonstrate a fundamental role for the α-isoform of the catalytic subunit of protein phosphatase-2A (PP2Ac) in regulating glioma immunogenicity. Genetic ablation of PP2Ac in glioma cells enhanced double-stranded DNA (dsDNA) production and cGAS-type I IFN signaling, MHC-I expression, and tumor mutational burden.

In coculture experiments, PP2Ac deficiency in glioma cells promoted dendritic cell (DC) cross-presentation and clonal expansion of CD8+ T cells. In vivo, PP2Ac depletion sensitized tumors to immune-checkpoint blockade and radiotherapy treatment. Single-cell analysis demonstrated that PP2Ac deficiency increased CD8+ T-cell, natural killer cell, and DC accumulation and reduced immunosuppressive tumor-associated macrophages.

Furthermore, loss of PP2Ac increased IFN signaling in myeloid and tumor cells and reduced expression of a tumor gene signature associated with worse patient survival in The Cancer Genome Atlas. Collectively, this study establishes a novel role for PP2Ac in inhibiting dsDNA-cGAS-STING signaling to suppress antitumor immunity in glioma.

SIGNIFICANCE: PP2Ac deficiency promotes cGAS-STING signaling in glioma to induce a tumor-suppressive immune microenvironment, highlighting PP2Ac as a potential therapeutic target to enhance tumor immunogenicity and improve response to immunotherapy.