Tumor-intrinsic Caspases-DFFB Axis Drives Immune Escape by Aggregating Cytosolic Histones to Suppress mtDNA-dependent cGAS Activation (PRJCA050552)
As a critical innate sensing platform, cyclic GMP-AMP (cGAMP) synthase (cGAS) can recognize cytosolic double-stranded DNA (dsDNA) to provoke anti-tumor immunity. However, it remains unclear why tumor cells frequently fail to activate the cGAS-STING pathway despite possessing substantial cytosolic DNA, and what role these DNA components play in regulating this pathway. Here, we observed that loss of tumor endogenous caspases reduced cytosolic genomic DNA (gDNA) aggregation without affecting mitochondrial (mtDNA) levels, and coincided with mtDNA-dependent tumor-intrinsic cGAS-STING activation. To circumvent the cleavage of cGAS by caspases, we overexpressed DFFB. Interestingly, although DFFB overexpression increased cytosolic gDNA levels, it resulted in reduced cGAS-STING activation. Mechanistically, we unexpectedly observed that cytosolic histones could bind to both gDNA and mtDNA. In contrast, cGAS-R222E, which is a cGAS mutant lacking histone-binding affinity, failed to bind cytosolic gDNA and also retained a certain level of cytosolic mtDNA binding affinity, thereby triggering mtDNA-dependent cGAS-STING activation. Furthermore, tumor cells harboring the cGAS-R222E mutant or lacking CASP3/7 exhibited markedly increased CD8+ T cell infiltration and enhanced CD8+ T cell- and NK cell-mediated antitumor immunity. Overall, our results revealed that tumor cells can hijack the intrinsic caspases-DFFB axis to induce the aggregation of cytosolic histone proteins, which in turn suppresses both mtDNA- and gDNA-mediated cGAS-STING activation and contributes to immune escape.