{"doi":"10.1101/2024.10.01.616069","title":"Proteolysis-targeting vaccines (PROTAVs) for robust combination immunotherapy of melanoma","abstract":"Abstract Protein/peptide subunit vaccines are promising to promote the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current protein/peptide vaccines elicit limited antitumor T cell responses, leading to suboptimal therapeutic efficacy. Here, we present proteolysis-targeting vaccines (PROTAVs) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of melanoma. PROTAVs are modular conjugates of protein/peptide antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, facilitating antigen proteolytic processing by proteasome, and thereby promoting antigen cross-presentation to T cells and potentiating CD8 + T cell responses. We developed a melanoma PROTAV using a tandem peptide of trivalent melanoma-associated antigens. Co-delivered by lipid nanoparticles (LNPs) with bivalent immunostimulant adjuvants, this PROTAV promotes the quantity and quality of melanoma-specific CD8 + T cells in mice. Further, combining PROTAV and ICB ameliorates the immunosuppressive melanoma microenvironment. As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% large Braf V600E melanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":504245,"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":0,"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":237025,"name":"Ting Su","orcid":"0000-0001-5254-1595","position":1,"is_corresponding":false},{"id":657641,"name":"Furong Cheng","orcid":null,"position":2,"is_corresponding":false},{"id":468679,"name":"Shurong Zhou","orcid":null,"position":3,"is_corresponding":false},{"id":504923,"name":"Xiang Liu","orcid":"0000-0002-8165-3294","position":4,"is_corresponding":false},{"id":1243588,"name":"Mi Wang","orcid":"0000-0003-2799-5987","position":5,"is_corresponding":false},{"id":1354360,"name":"You Xu","orcid":"0009-0008-3668-9299","position":6,"is_corresponding":false},{"id":1354361,"name":"Ri Tang","orcid":"0000-0003-0137-2917","position":7,"is_corresponding":false},{"id":572370,"name":"Shimiao Liao","orcid":"0000-0001-9427-9265","position":8,"is_corresponding":false},{"id":452060,"name":"Jordan Dailey","orcid":null,"position":9,"is_corresponding":false},{"id":1354808,"name":"Guolan Xiao","orcid":null,"position":10,"is_corresponding":false},{"id":1354362,"name":"Chunpeng Yang","orcid":"0000-0001-7075-3356","position":11,"is_corresponding":false},{"id":1337410,"name":"Hanning Wen","orcid":null,"position":12,"is_corresponding":false},{"id":1354363,"name":"Weijia Zheng","orcid":"0009-0009-2620-7919","position":13,"is_corresponding":false},{"id":262021,"name":"Bo Wen","orcid":"0000-0002-8337-220X","position":14,"is_corresponding":false},{"id":298426,"name":"Katarzyna M. Tyc","orcid":"0000-0002-3850-6934","position":15,"is_corresponding":false},{"id":437424,"name":"Jinze Liu","orcid":"0000-0003-0555-9412","position":16,"is_corresponding":false},{"id":262031,"name":"Duxin Sun","orcid":"0000-0002-6406-2126","position":17,"is_corresponding":false},{"id":262043,"name":"Shaomeng Wang","orcid":"0000-0002-8782-6950","position":18,"is_corresponding":false},{"id":237026,"name":"Guizhi Zhu","orcid":"0000-0002-2945-7982","position":19,"is_corresponding":false},{"id":1152856,"name":"Qiyan Wang","orcid":"0000-0001-6379-7879","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:10:35.597333Z","pmid":"39574605","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":[]}