{"doi":"10.1126/sciadv.adi2012","title":"Tumor cell–intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling","abstract":"Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.","journal":"Science Advances","year":2024,"id":422793,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"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":431626,"name":"Erik Rasbach","orcid":"0000-0002-0807-3058","position":1,"is_corresponding":false},{"id":620910,"name":"Markus V. Heppt","orcid":"0000-0003-4603-1825","position":2,"is_corresponding":false},{"id":892924,"name":"Praveen Kumar Singh","orcid":"0000-0002-8188-2636","position":3,"is_corresponding":false},{"id":1206812,"name":"Zsófi Kulcsár","orcid":null,"position":4,"is_corresponding":false},{"id":1206011,"name":"Julia Holzgruber","orcid":"0000-0002-7804-9387","position":5,"is_corresponding":false},{"id":347235,"name":"Asmi Chakraborty","orcid":"0000-0002-6528-8602","position":6,"is_corresponding":false},{"id":892925,"name":"Kyla Mucciarone","orcid":"0000-0003-3755-2370","position":7,"is_corresponding":false},{"id":1217763,"name":"Sonja Kleffel","orcid":null,"position":8,"is_corresponding":false},{"id":892927,"name":"Anne Brandenburg","orcid":"0000-0002-8409-7174","position":9,"is_corresponding":false},{"id":773001,"name":"Wolfram Hoetzenecker","orcid":"0000-0003-4710-0642","position":10,"is_corresponding":false},{"id":1217237,"name":"Nuh N. Rahbari","orcid":"0000-0002-4703-9039","position":11,"is_corresponding":false},{"id":270590,"name":"James A. DeCaprio","orcid":"0000-0002-0896-167X","position":12,"is_corresponding":false},{"id":270584,"name":"Manisha Thakuria","orcid":"0000-0002-9024-9090","position":13,"is_corresponding":false},{"id":40507,"name":"Gëorge F. Murphy","orcid":"0000-0001-9362-5146","position":14,"is_corresponding":false},{"id":596329,"name":"Matthew R. Ramsey","orcid":"0000-0003-2402-8502","position":15,"is_corresponding":false},{"id":899460,"name":"Christian Posch","orcid":"0000-0003-0296-3567","position":16,"is_corresponding":false},{"id":892931,"name":"Steven R. Barthel","orcid":"0000-0003-2107-4570","position":17,"is_corresponding":false},{"id":892921,"name":"Tobias Schatton","orcid":"0000-0003-1386-680X","position":18,"is_corresponding":false},{"id":892923,"name":"Christina Martins","orcid":"0000-0002-9160-1017","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:57:51.642883Z","pmid":"38241371","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":[]}