{"doi":"10.3390/cancers17182998","title":"Mechanistic Insights into Proglumide’s Role in Immune Cell Efficacy and Response to Immune Checkpoint Inhibitor Therapy in Hepatocellular Carcinoma","abstract":"BACKGROUND: New strategies are needed to improve the response to immune checkpoint inhibitors for the treatment of hepatocellular carcinoma. METHODS: Mice bearing HCC tumors were treated with PBS (control), a PD-1 antibody (PD-1Ab), proglumide, or the combination of proglumide and the PD-1Ab. The tumor microenvironment (TME) was evaluated histologically for fibrosis and by immunohistochemistry for immune cells. To investigate the mechanisms involved in T-cell efficiency, mouse spleen cells were isolated and examined for T-cell exhaustion markers and cytokine release. The mouse microbiome was analyzed using whole-genome sequencing before therapy and at the end of the study. RESULTS: The combination of proglumide with a PD-1Ab decreased tumoral fibrosis better than monotherapy, and altered the immune cell signature in the TME by decreasing M2-polarized macrophages and increasing the influx of CD8+ T-cells. Proglumide monotherapy or in combination with the PD-1Ab decreased T-cell exhaustion markers and improved cytokine release. The combination therapy resulted in changes to the microbiome, including increased beneficial bacteria and genera known to enhance the efficacy of ICIs. CONCLUSIONS: Co-administration of proglumide with ICIs resulted in remodeling of the TME, changing a \"cold\" tumor to a \"hot\" immune-responsive tumor, activating T-cells, and altering the host microbiome to a population of bacteria that are beneficial.","journal":"Cancers","year":2025,"id":554139,"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":1,"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":404336,"name":"Hong Cao","orcid":"0000-0002-8618-4896","position":1,"is_corresponding":false},{"id":748384,"name":"Wenqiang Chen","orcid":"0000-0001-6148-5708","position":2,"is_corresponding":false},{"id":927475,"name":"Wenyu Dou","orcid":"0000-0003-2101-5175","position":3,"is_corresponding":false},{"id":927476,"name":"Hong‐Bin Fang","orcid":"0000-0002-6173-9082","position":4,"is_corresponding":false},{"id":404341,"name":"Jill P. Smith","orcid":"0000-0002-0835-4802","position":5,"is_corresponding":false},{"id":1451444,"name":"Priyanka S. Doneparthi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:54:45.872391Z","pmid":"41008842","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":[]}