{"doi":"10.1172/jci.insight.184435","title":"Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity","abstract":"Uracil DNA glycosylase (UNG) excises uracil and 5-fluorouracil bases from DNA and is implicated in fluorodeoxyuridine (FdU) resistance. Here we explore the effects of inhibiting UNG activity, or depleting the UNG protein, in 2 mouse syngeneic models for colorectal cancer. Overexpressing the small UNG inhibitor protein (UGI) in mismatch repair-deficient (MMR-deficient) MC38 cells injected into C57BL/6J mice delayed tumor growth and prolonged survival when combined with FdU. Combining UNG inhibition with FdU numerically increased CD4+ T lymphocytes and B cells compared with FdU or UNG inhibition alone, suggesting an immune component to the effects. In contrast, shRNA depletion of UNG in the absence of FdU treatment resulted in 70% of mice clearing their tumors, and a 3-fold increase in overall survival compared with FdU. Analysis of MC38 tumor-infiltrating immune cells showed UNG depletion increased monocyte and dendritic cell populations, with CD8+ T cells also numerically increased. shRNA depletion of UNG in MMR-proficient CT-26 cells injected into BALB/c mice produced minimal benefit; the addition of anti-PD-1 antibody synergized with UNG depletion to increase survival. Cytotoxic T cell depletion abolished the benefits of UNG depletion in both models. These findings suggest UNG inhibition and/or depletion could enhance antitumor immune responses in humans.","journal":"JCI Insight","year":2025,"id":550824,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9646,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":758575,"name":"Brandon E. Smith","orcid":"0000-0002-4207-8389","position":1,"is_corresponding":false},{"id":1446726,"name":"Thanh J. Nguyen","orcid":null,"position":2,"is_corresponding":false},{"id":1373162,"name":"Alens Valentin","orcid":"0009-0003-4348-4527","position":3,"is_corresponding":false},{"id":653229,"name":"Soren Charmsaz","orcid":"0000-0002-9148-9870","position":4,"is_corresponding":false},{"id":653230,"name":"Nicole Groß","orcid":"0000-0002-8936-207X","position":5,"is_corresponding":false},{"id":860488,"name":"Sarah M. Shin","orcid":"0000-0002-7658-5899","position":6,"is_corresponding":false},{"id":860490,"name":"Alexei Hernandez","orcid":"0000-0002-6044-2631","position":7,"is_corresponding":false},{"id":317428,"name":"Won Jin Ho","orcid":"0000-0003-2644-5086","position":8,"is_corresponding":false},{"id":263709,"name":"Srinivasan Yegnasubramanian","orcid":"0000-0003-0744-6606","position":9,"is_corresponding":false},{"id":454788,"name":"James T. Stivers","orcid":"0000-0003-2572-7807","position":10,"is_corresponding":false},{"id":240667,"name":"Eric S. Christenson","orcid":"0000-0001-5261-6083","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:54:20.915388Z","pmid":"40663394","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}