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To thrive, cancer cells must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of repeat elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution, and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNAs (dsRNAs) and trigger retinoic-acid-inducible gene I (RIG-I)-like-receptor (RLR)-associated type-I interferon (IFN) signaling. Such Alu-derived dsRNAs also anti-correlated with pro-tumorigenic macrophage infiltration in late stage tumors. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant TP53 tumors, ORF1p from long interspersed nuclear element (LINE)-1 preferentially binds Alus and decreases their expression, whereas adenosine deaminases acting on RNA 1 (ADAR1) editing primarily reduces dsRNA formation in wild-type TP53 tumors. Depletion of either LINE-1 ORF1p or ADAR1 reduced tumor growth in vitro. The fact that tumors utilize multiple pathways to mitigate immunostimulatory repeats implies the stress from their expression is a fundamental phenomenon to which PDAC, and likely other tumors, adapt., Competing Interests: Declaration of interests B.D.G. received honoraria from Merck, Bristol Meyers Squibb (BMS), and Chugai Pharmaceuticals; research funding from BMS and Merck; and has been a compensated consultant for Darwin Health, Merck, PMV Pharma, Shennon Biotechnologies, Synteny AI, and ROME Therapeutics, of which he is a co-founder. A.S. has consulted for PMV Pharma and ROME Therapeutics, and he holds stock options of ROME Therapeutics. D.T.T. has received consulting fees from ROME Therapeutics, Sonata Therapeutics, Leica Biosystems Imaging, PanTher Therapeutics, and abrdn. D.T.T is a founder and has equity in ROME Therapeutics, PanTher Therapeutics, and TellBio, Inc., which is not related to this work. D.T.T is on the advisory board with equity for ImproveBio, Inc. D.T.T. has recieved honorariums from Astellas, AstraZeneca, Moderna, and Ikena Oncology that are not related to this work. D.T.T. recieves research support from ACD-Biotechne, AVA LifeScience GmbH, Incyte Pharmaceuticals, Sanofi, and Astellas, which was not used in this work. D.T.T.’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. S.W.L. is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus, Inc., PMV Pharmaceuticals, Faeth Therapeutics, and Fate Therapeutics. J.L. received research funding from ROME Therapeutics, Ribon Therapeutics, and Refeyn; he received compensation from Transposon, ROME, and Oncolinea. C.A.I.-D. has received research support from Bristol Meyers Squibb., (Copyright © 2024. Published by Elsevier Inc.)