{"doi":"10.3390/cancers17193187","title":"Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer","abstract":"BACKGROUND: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood. METHODS: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine. RESULTS: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells. CONCLUSIONS: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance.","journal":"Cancers","year":2025,"id":534878,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.944,"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":1418009,"name":"Huan Qu","orcid":"0000-0003-0338-7223","position":1,"is_corresponding":false},{"id":295685,"name":"Joy C. Yang","orcid":"0000-0001-9162-481X","position":2,"is_corresponding":false},{"id":1016480,"name":"Wei Fan","orcid":"0000-0002-2735-9350","position":3,"is_corresponding":false},{"id":1418010,"name":"Junwei Zhao","orcid":"0000-0003-1595-6278","position":4,"is_corresponding":false},{"id":316273,"name":"Menghuan Tang","orcid":null,"position":5,"is_corresponding":false},{"id":946129,"name":"Leyi Wang","orcid":"0009-0008-7297-0643","position":6,"is_corresponding":false},{"id":1026001,"name":"Christopher Nip","orcid":null,"position":7,"is_corresponding":false},{"id":1418011,"name":"Hui Li","orcid":"0000-0002-5822-2795","position":8,"is_corresponding":false},{"id":295690,"name":"Allen C. Gao","orcid":"0000-0002-5966-9038","position":9,"is_corresponding":false},{"id":237448,"name":"Kit S. Lam","orcid":"0000-0002-3076-6969","position":10,"is_corresponding":false},{"id":642437,"name":"Marc Dall’Era","orcid":"0000-0002-2301-2683","position":11,"is_corresponding":false},{"id":237446,"name":"Yuanpei Li","orcid":"0000-0002-4015-646X","position":12,"is_corresponding":false},{"id":295691,"name":"Chengfei Liu","orcid":"0000-0002-2452-8788","position":13,"is_corresponding":false},{"id":871336,"name":"Pengfei Xu","orcid":"0000-0002-9401-9487","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:51:52.019261Z","pmid":"41097714","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":[]}