{"doi":"10.1007/s00262-025-04180-3","title":"Single-cell transcriptomic analyses provide insights into SPP1+ TAM-mediated immune suppression and CD8+ T cell dysfunction in lung cancer","abstract":null,"journal":"Cancer Immunology, Immunotherapy","year":2025,"id":619013,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1568624,"name":"Tengyue Zhang","orcid":null,"position":1,"is_corresponding":false},{"id":1597274,"name":"Qitai Zhao","orcid":null,"position":2,"is_corresponding":false},{"id":1597275,"name":"Mingming You","orcid":null,"position":3,"is_corresponding":false},{"id":218111,"name":"Jinyan Liu","orcid":"0000-0003-0504-2181","position":4,"is_corresponding":false},{"id":700554,"name":"Yi Zhang","orcid":"0009-0002-1010-9205","position":5,"is_corresponding":false},{"id":1597273,"name":"Rahma Taher Almgrami","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Single-cell transcriptomic analyses provide insights into SPP1+ TAM-mediated immune suppression and CD8+ T cell dysfunction in lung cancer","abstract":"Metastatic lung carcinoma poses considerable treatment difficulties. It exhibits cellular characteristics that differ from those of early-stage cancer. Immunotherapy demonstrates enhanced hope for patients with advanced and metastatic lung cancer. Tumor-associated macrophages (TAMs) may be a contributing factor that diminishes the effectiveness of immunotherapy. Secreted phosphoprotein 1 (SPP1) + TAMs are considered to possess immunosuppressive characteristics, as their interaction with CD8 + T lymphocytes results in the exhaustion of these cells. We analyzed single-cell RNA sequencing datasets of lung cancer metastases in order to examine the development of brain metastatic tumors. Furthermore, the cell–cell interactions between SPP1 + TAM cells and CD8 + T cells within primary and brain metastatic cancers were systematically compared. Additionally, we utilized a flow cytometer and immunofluorescence to demonstrate how SPP1 affects the function of CD8 + T cells. In vitro, we generated SPP1-overexpressing macrophages and performed qPCR, Western blot, and co-culture assays with or without anti-SPP1 or anti-A2AR treatment to evaluate immunosuppressive effects. The results demonstrated that the proportions of immune cells in metastatic brain tissues are lower, while the infiltration of macrophages is higher. SPP1 + TAMs contribute to immune suppression in lung cancer by limiting the activation of CD8 + T cells and cytokine production. Anti-SPP1 treatment positively impacts CD8 + T cell function, counteracting SPP1-induced dysfunction and facilitating the production of cytokines. SPP1 overexpression in macrophages enhanced their immunosuppressive phenotype by upregulating CD73 and cytokines such as IL-10 and TGF-β, leading to impaired CD8⁺ T cell function via A2AR signaling; notably, neutralization of SPP1 or A2AR successfully restored CD8⁺ T cell activity. Our findings characterize the immunological environment of both primary and metastatic lung cancer, highlighting SPP1-mediated immune suppression as a potential therapeutic target to restore T cell responses. Preclinical data demonstrate that Anti-SPP1 antibodies can reverse T cell exhaustion and enhance immune responses in lung cancer.","is_dataset_classified":null,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41021043","pmcid":"PMC12480184","openalex_id":"https://openalex.org/W4414588437","authors":[],"funders":[{"funder_name":"Postdoctoral Fellowship Program","grant_id":"GZC20232435","title":null},{"funder_name":"Medical Science and Technology Research Project of Henan Province","grant_id":"252102311163","title":null},{"funder_name":"National Natural Science Foundation of China Joint Fund Key Support Project","grant_id":"U24A20734","title":null},{"funder_name":"Key Special Project for International Science and Technology Innovation Cooperation between Governments under the National Key R&D Program","grant_id":"2022YFE0141000","title":null},{"funder_name":"National Natural Science Foundation of China–General Project","grant_id":"82272873","title":null}],"total_grants":5,"fwci":4.8844,"citation_percentile":0.9604045,"influential_citations":0,"citation_trend":[{"year":2026,"count":12}],"oa_status":"gold","license":"cc-by-nc-nd","oa_locations":[{"url":"https://link.springer.com/content/pdf/10.1007/s00262-025-04180-3.pdf","host_type":"journal"},{"url":"https://link.springer.com/content/pdf/10.1007/s00262-025-04180-3.pdf","host_type":"publisher"},{"url":"https://link.springer.com/article/10.1007/s00262-025-04180-3/fulltext.html","host_type":"publisher"},{"url":"https://doi.org/10.1007/s00262-025-04180-3","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41021043","host_type":"repository"},{"url":"https://doaj.org/article/19fe41f52af046eaa38c81ee170cb7c4","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12480184","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12480184/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12480184","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12480184?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Protein Tyrosine Phosphatases","Phagocytosis and Immune Regulation","Immune cells in cancer","Lung Neoplasms","CD8-Positive T-Lymphocytes","Humans","Single-Cell Analysis","Osteopontin","Tumor-Associated Macrophages","Gene Expression Profiling","Brain Neoplasms","Transcriptome","Animals","Tumor Microenvironment"],"mesh_terms":["Tumor-Associated Macrophages","Animals","Brain Neoplasms","Humans","Lung Neoplasms","CD8-Positive T-Lymphocytes","Gene Expression Profiling","Osteopontin","Single-Cell Analysis","Tumor Microenvironment","Transcriptome"],"keywords":["Immune system","Lung cancer","T cell","Transcriptome","Immunotherapy","Antibody","Lung","Brain metastasis","Cd73","Spp1","A2ar","Cd8+ T Cell Dysfunction","Spp1+ Tams"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"geo"},{"name":"gen"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T05:45:12.075919Z","pmid":null,"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":[]}