Repeat element viral mimicry is a common feature in pancreatic ductal adenocarcinoma (PDAC) that requires mechanisms to manage this repeat “viral” load and attenuate innate immune responses. In this study, we show that the long interspersed nuclear element 1 (LINE-1) open reading frame 1 protein (ORF1p) in PDAC cells plays a role in shielding repeat RNAs from activating a pathogen recognition receptor–mediated antiviral response that is independent of retrotransposition. Suppression of ORF1p using short hairpin RNA induces innate immune responses through the double-stranded RNA (dsRNA) sensors RIG-I and MAVS. Low ORF1p PDAC cell lines have suppressed expression of pathogen recognition receptors demonstrating convergent mechanisms to suppress innate immune signaling. Localization of ORF1p in processing bodies with the dsRNA helicase MOV10 was found to be important for these antiviral responses. Loss of ORF1p resulted in significant growth reduction in tumorspheres and mouse xenografts with an enriched epithelial cell state, and high ORF1p expression was associated with worsened survival in a cohort of human patients with PDAC.

Significance:

This study uncovers PDAC-specific mechanisms that dampen immune responses to viral-repeat RNA via long interspersed nuclear element 1 ORF1p. Suppression of ORF1p activates antiviral responses, reducing tumor growth and epithelial–mesenchymal transition. High ORF1p expression correlates with poor prognosis, highlighting its potential as a therapeutic target for PDAC.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
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First page of LINE-1 ORF1p Mimics Viral Innate Immune Evasion Mechanisms in Pancreatic Ductal Adenocarcinoma<alt-title alt-title-type="short">LINE-1 ORF1p Mimics Viral Innate Immune Evasion in PDAC</alt-title>

Supplementary data

Supplementary Table S1

Supplementary Table S1. List of proteins localized in PBs.

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Supplementary Table S2

Supplementary Table S2. Classification of FOVs based on LINE-1 ORF1p expression.

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Supplementary Table S3

Supplementary Table S3. Key resources table

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Supplementary Figures S1-S7

Supplementary Figure S1. LINE-1 ORF1p function in PDAC and other cell lines. Supplementary Figure S2. Titration of Dox concentration to rescue ORF1p expression and evaluation of micronuclei-mediated STING activation. Supplementary Figure S3. ORF1p knockdown sensitizes repeat RNA-induced IFN response. Supplementary Figure S4. ORF1p cellular localization and evaluation of RNA editing protein function. Supplementary Figure S5. EM-related gene expression and response to drugs upon ORF1 knockdown. Supplementary Figure S6. ORF1 knockdown in vivo suppresses tumor progression by altering the TME. Supplementary Figure S7. Analysis of single-cell spatial neighborhoods.

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