{"doi":"10.1101/2023.08.07.552383","title":"Overcome Prostate Cancer Resistance to Immune Checkpoint Therapy with Ketogenic Diet-Induced Epigenetic Reprogramming","abstract":"Abstract Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we developed a syngeneic murine PCa model with acquired ICB resistance. Using this model, synergistic efficacy was achieved by combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or supplementation of ketone body β-hydroxybutyrate (BHB, endogenous HDACi) via 1,3-butanediol-admixed food. CKD and BHB supplementation delayed PCa tumors as monotherapy, and both BHB and adaptive immunity are required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that the HDACi and ketogenesis-enhanced ICB therapy involves cancer-cell-intrinsic (upregulated MHC class I molecules) and extrinsic mechanisms (CD8 + T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophils). Overall, these findings underscore the potential of using HDACi and optimized KD to enhance ICB therapy for PCa.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391926,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":449675,"name":"Sharif Rahmy","orcid":"0000-0002-7825-7186","position":1,"is_corresponding":false},{"id":950901,"name":"Dailin Gan","orcid":"0000-0003-0535-1259","position":2,"is_corresponding":false},{"id":918388,"name":"Yini Zhu","orcid":"0000-0002-9592-2053","position":3,"is_corresponding":false},{"id":1165619,"name":"M.J. Manyak","orcid":null,"position":4,"is_corresponding":false},{"id":242234,"name":"Jun Li","orcid":"0000-0003-4353-5761","position":5,"is_corresponding":false},{"id":302042,"name":"Xuemin Lu","orcid":"0009-0008-0060-8346","position":6,"is_corresponding":false},{"id":274882,"name":"Xin Lü","orcid":"0000-0002-0284-6478","position":7,"is_corresponding":false},{"id":908945,"name":"Seán Murphy","orcid":"0000-0002-6582-4065","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:18:52.232318Z","pmid":"37609341","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":[]}