{"doi":"10.1016/j.celrep.2024.114532","title":"Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response","abstract":"Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3 + regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4 −/− were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.","journal":"Cell Reports","year":2024,"id":438761,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":900961,"name":"Jisun Kim","orcid":"0000-0001-6884-2042","position":1,"is_corresponding":false},{"id":486697,"name":"Do‐Sung Kim","orcid":"0000-0002-2039-5295","position":2,"is_corresponding":false},{"id":362164,"name":"Alhaji H. Janneh","orcid":"0000-0001-5959-6126","position":3,"is_corresponding":false},{"id":640340,"name":"Han Gyul Lee","orcid":"0009-0003-8351-9130","position":4,"is_corresponding":false},{"id":877843,"name":"Firdevs Cansu Atilgan","orcid":"0000-0001-9055-9497","position":5,"is_corresponding":false},{"id":877844,"name":"Natalia V. Oleinik","orcid":"0000-0002-6658-9140","position":6,"is_corresponding":false},{"id":640341,"name":"Mohamed Faisal Kassir","orcid":"0000-0003-3501-1802","position":7,"is_corresponding":false},{"id":231086,"name":"Özge Saatci","orcid":"0000-0002-0124-044X","position":8,"is_corresponding":false},{"id":433527,"name":"Paramita Chakraborty","orcid":"0000-0002-0320-8697","position":9,"is_corresponding":false},{"id":231093,"name":"Ünal Metin Tokat","orcid":"0000-0003-0026-368X","position":10,"is_corresponding":false},{"id":1248888,"name":"Salih Gencer","orcid":"0000-0002-7412-5610","position":11,"is_corresponding":false},{"id":733913,"name":"Breege V. Howley","orcid":"0000-0001-9790-8880","position":12,"is_corresponding":false},{"id":321625,"name":"Philip H. Howe","orcid":"0000-0002-1358-1313","position":13,"is_corresponding":false},{"id":242937,"name":"Shikhar Mehrotra","orcid":"0000-0002-5411-9504","position":14,"is_corresponding":false},{"id":231105,"name":"Özgür Şahin","orcid":"0000-0002-8033-7089","position":15,"is_corresponding":false},{"id":593575,"name":"Besim Öğretmen","orcid":"0000-0002-1019-5660","position":16,"is_corresponding":false},{"id":1248887,"name":"Wyatt Wofford","orcid":"0000-0001-8115-464X","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T02:00:43.618468Z","pmid":"39046874","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":[]}