ArticleHuman mutation2026
PLSCR3 Deficiency Triggers mtDNA-Driven cGAS-STING Activation to Potentiate Antitumor Immunity in Colorectal Cancer.
Article in Human mutation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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Who cites it
2 citing papers in PubMed.
- PLSCR3 Deficiency Triggers mtDNA-Driven cGAS-STING Activation to Potentiate Antitumor Immunity in Colorectal Cancer.Human mutation · 2026Article
- The mitochondrial DNA-cGAS-STING axis in colorectal cancer: a focused review of context-dependent roles and therapeutic opportunities.Frontiers in molecular biosciences · 2026Review
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Authors and funding
11 authors.
Funding
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Abstract
Background: Immunotherapy efficacy in colorectal cancer (CRC) is largely restricted to microsatellite instability-high (MSI-H) tumors, highlighting an urgent need to overcome resistance in microsatellite-stable (MSS) CRC. Mitochondrial DNA (mtDNA) leakage activates the cGAS-STING pathway, a potent inducer of antitumor immunity. However, endogenous regulators constraining mtDNA release in CRC, particularly within the inner mitochondrial membrane (IMM), remain poorly defined. Methods: In CRC cohorts from TCGA, integrated bioinformatics analysis identified dysregulated mitochondria-associated genes exhibiting significant differential expression and survival outcomes. Phospholipid Scramblase 3 (PLSCR3) emerged as the prime candidate. Functional validation employed siRNA knockdown and CRISPR/Cas9 knockout in human (HT29) and mouse (CT26) CRC cell lines. Mitochondrial integrity was evaluated via JC-1 membrane potential assay, oxygen consumption rate (OCR) measurement, and cytosolic mtDNA quantification. cGAS-STING activation was measured by 2 Results: PLSCR3 was selected for further study because it fulfilled three criteria simultaneously: differential expression in CRC, significant association with survival in univariate analysis, and established mitochondrial localization. PLSCR3 deficiency disrupted mitochondrial integrity, causing membrane depolarization, impaired respiration, and significant cytosolic mtDNA accumulation. This mtDNA leakage robustly activated the cGAS-STING pathway, evidenced by increased 2 Conclusion: Our study identifies PLSCR3 as a previously unrecognized negative regulator of mtDNA-associated cGAS-STING activation in CRC. By maintaining mitochondrial homeostasis and limiting mtDNA leakage, PLSCR3 constrains innate immune signaling and reduces sensitivity to anti-PD-1 therapy in the CT26 model. These findings establish PLSCR3 as a promising therapeutic target to enhance immunotherapy responses in CRC.
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