POLQ-driven repair scars shape the immunogenic landscape of homologous recombination-deficient pancreatic cancer

ABSTRACT Pancreatic cancer (PC) is broadly resistant to immune checkpoint blockade, although a subset of homologous recombination-deficient (HRD) tumors exhibits durable immune engagement. The genomic features that distinguish these immune-responsive tumors from immune-inert HRD tumors remain poorly understood. Here we identify a microhomology-mediated end joining (MMEJ) repair scar, the MMEJ Deletion Footprint (MDF), as a genomic readout of POLQ-associated error-prone repair that enriches for frameshift indels. Across the multi-omic discovery cohort integrating tumor genomics, single-nucleus transcriptomics and spatial immune profiling, MDF-high HRD PC exhibited increased frameshift-indel-derived neoantigens and interferon programs. MDF was further associated with remodeling of the myeloid compartment toward MHC II-high dendritic cell-like antigen-presenting macrophage states and the immune synapse architecture marked by increased spatial interaction between APC-like macrophages and cytotoxic CD8+ T cells. These tissue-level features aligned with a functional trajectory shift of CD8+ T cells, consistent with effective anti-tumor immunity and was associated with favorable clinical outcomes of patients. Together, our findings position MMEJ-linked repair scarring as actionable biology that connects an HRD genotype to immune organization and suggests rational immunotherapy combinations that may enhance antigen presentation and myeloid activation to extend durable benefit in HRD-lineage cancers. Competing Interest Statement W.P. reports research funding to his institution from Merck, Astellas, Lepu Biopharma, Amgen, and Revolution Medicines; consulting for Astellas, EXACT Therapeutics, Revolution Medicines, Innovent Biologics, Regeneron Pharmaceuticals, KeyQuest, TD Cowen, and AlphaSights; CME honoraria from American Physician Institute, Curio, Integrity, Physicians Education Resource, and Aptitude Health; and travel support from Amgen and DAVA Oncology. M.H. reports honoraria from Pierre Fabre, AstraZeneca, Amgen, and Viatris, research funding from Servier, and travel support from Astellas. H.Z. is an employee of Valar Labs and owns stock in Revolution Medicines. A.M.V. reports consulting through a spouse for AstraZeneca and Paige.AI and intellectual property rights with SOPHiA Genetics. D.K. reports honoraria from Ipsen and Revolution Medicines and consulting for Precision AI Solutions Inc. K.H.Y. reports relationships with Ipsen Pharma. D.N.K. reports research support and intellectual property associated with Merck, consulting fees from AbbVie, Akamis Bio, Celldex, PrimeFour Therapeutics, Replimune, and Sanofi, sponsored research agreements with Ankyra and Encapsulate, and is an inventor on patents related to interleukin 10, in situ vaccination, nanoparticle therapeutics, toll like receptor agonists, and CD40. R.C. serves on the scientific advisory boards of Sanavia Oncology and LevitasBio and is a consultant for the Gerson Lehrman Group. M.J.P. reports consulting or advisory roles for AstraZeneca, Merus, Merck, Moderna, Astellas, Serna Bio, Revolution Medicines, Canopy Cancer Collective, and Novocure; advisory board roles for Astellas, Merck, Trisalus, RenovoRx, and Sanofi; travel support from Astellas, RenovoRx, Merus, and Novocure; stock ownership in Perthera; and research funding to his institution from Arcus Bio, Ideaya, Repare Therapeutics, Novartis, Pfizer, Merck, Amgen, RenovoRx, Boehringer Ingelheim, Astellas, Takeda, Actuate, MEI Pharma, Ikena, Lilly, and Parabilis. M.F.B. reports consulting for AstraZeneca and Paige.AI and intellectual property rights with SOPHiA Genetics. V.B. reports relationships with Genentech, Merck, and AbbVie. D.P. serves on the scientific advisory board of Insitro. N.R. reports research funding from Pfizer. E.M.O. reports research funding to her institution from Arcus, Genentech/Roche, BioNTech, Incyte, AstraZeneca, Elicio Therapeutics, Digestive Care, Agenus, Amgen, Revolution Medicines, and Tango Therapeutics; and participation in advisory boards or DSMBs (uncompensated) for Arcus, Amgen, AstraZeneca, Alligator BioSciences, Pfizer, Agenus, BioNTech, Ipsen, Ikena, Merck, Immuneering, Moma Therapeutics, Novartis, Astellas, Bristol Myers Squibb, Revolution Medicines, Regeneron, Tango Therapeutics, Cantargia, BridgeBio, and Oncolytics. Travel support has been received from BioNTech, Arcus, and Pfizer. All other authors declare no competing interests.