{"doi":"10.1016/j.celrep.2024.114907","title":"PD-1 endocytosis unleashes the cytolytic potential of checkpoint blockade in tumor immunity","abstract":"PD-1 immune checkpoint blockade (ICB) is a key cancer treatment. While blocking PD-1 binding to ligand is known, the role of internalization in enhancing ICB efficacy is less explored. Our study reveals that PD-1 internalization helps unlock ICB's full potential in cancer immunotherapy. Anti-PD-1 induces 50%–60% surface PD-1 internalization from human and mouse cells, leaving low to intermediate levels of resistant receptors. Complexes then appear in early and late endosomes. Both CD4 and CD8 T cells, especially CD8 + effectors, are affected. Nivolumab outperforms pembrolizumab in human T cells, while PD-1 internalization requires crosslinking by bivalent antibody. While mono- and bivalent anti-PD-1 inhibit tumor growth with CD8 tumor-infiltrating cells expressing increased granzyme B, bivalent antibody is more effective where the combination of steric blockade and endocytosis induces greater CD8 + T cell tumor infiltration and the expression of the cytolytic pore protein, perforin. Our findings highlight an ICB mechanism that combines steric blockade and PD-1 endocytosis for optimal checkpoint immunotherapy.","journal":"Cell Reports","year":2024,"id":425281,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9455,"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":1222901,"name":"Andres Oroya","orcid":"0000-0002-9012-3041","position":1,"is_corresponding":false},{"id":994563,"name":"Nikhil Ponnoor Anto","orcid":"0000-0001-9449-5654","position":2,"is_corresponding":false},{"id":1223390,"name":"Meriem Bachais","orcid":null,"position":3,"is_corresponding":false},{"id":608918,"name":"Christopher E. Rudd","orcid":"0000-0001-5295-9019","position":4,"is_corresponding":false},{"id":1223389,"name":"Elham Ben Saad","orcid":null,"position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T01:58:26.927596Z","pmid":"39471174","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":[]}