{ "abstract": "Innate immune cells constitute the majority of the tumor microenvironment (TME), where they mediate both natural anti-tumor immunity and immunotherapy responses. While single-cell T- and B-cell receptor sequencing has provided fundamental insights into the clonal dynamics of human adaptive immunity, the lack of appropriate tools has precluded similar analysis of innate immune cells. Here, we describe a method that leverages somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between single cells across cell types in native human tissues. We jointly sequenced single-cell transposase-accessible chromatin and mtDNA to profile n =124,958 cells from matched tumor, non-involved lung tissue (NILT), and peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients, as well as n =93,757 cells from matched tumor and peripheral blood of ovarian cancer patients. Single-cell concomitant profiling of lineage and cell states of thousands of immune cells resolved clonality across cell types, tissue sites, and malignancies. Clonal tracing of innate immune cells demonstrates that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally linked to both circulating and tissue-infiltrating monocytes. Further, we identify distinct DC-biased and macrophage-biased myeloid clones, enriched in the tumor and NILT, respectively, and find that their circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting that myeloid differentiation fate may be predetermined before TME infiltration. These results delineate the clonal pathways of intratumoral myeloid cell recruitment and differentiation in human cancer and suggest that remodeling of the tumor myeloid compartment may be peripherally programmed.", "abstract_shown": true, "affiliations": [ "Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA. Electronic address: liuv@stanford.edu", "Department of Genetics, Stanford University, Stanford, CA, USA", "Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA", "Department of Pathology, Stanford University, Stanford, CA, USA", "Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA", "Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA", "Department of Bioengineering, Stanford University, Stanford, CA, USA", "Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA", "Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA", "Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA", "Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 1005, USA", "Department of Genetics, Stanford University, Stanford, CA 94305, USA", "Center for Immunotherapy Design, Stanford University, Stanford, CA, USA", "Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10178 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany", "Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany", "Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany", "Department of Pathology, Stanford University, Stanford, CA 94305, USA", "Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: lareauc@mskcc.org", "Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. Electronic address: satpathy@stanford.edu", "Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA" ], "article_type": null, "arxiv": null, "author_total": 18, "authors": [ { "affs": [ 0, 1 ], "name": "Vincent Liu", "orcid": "0000-0002-6790-6603" }, { "affs": [ 2, 3 ], "name": "Katalin D. Sandor", "orcid": "0000-0003-2892-4865" }, { "affs": [ 2, 3 ], "name": "Patrick Yan", "orcid": "0000-0001-6124-1615" }, { "affs": [ 4, 1 ], "name": "Zhuang Miao", "orcid": "0000-0002-6200-2306" }, { "affs": [ 2, 3 ], "name": "Yajie Yin", "orcid": "0000-0002-2220-005X" }, { "affs": [ 2, 3 ], "name": "Robert R. Stickels", "orcid": "0000-0003-4326-4084" }, { "affs": [ 5, 6 ], "name": "Andy Y. Chen", "orcid": "0000-0002-5018-355X" }, { "affs": [ 2, 3 ], "name": "Kamir J. Hiam-Galvez", "orcid": "0000-0002-1956-0257" }, { "affs": [ 7, 8 ], "name": "Jacob C. Gutierrez", "orcid": "0000-0003-4581-3534" }, { "affs": [ 2, 3 ], "name": "Wenxi Zhang", "orcid": "0000-0002-8863-4838" }, { "affs": [ 9, 10 ], "name": "Sairaj M. Sajjath", "orcid": "0000-0002-7156-3279" }, { "affs": [ 11, 1 ], "name": "Raeline Valbuena", "orcid": "0000-0001-7877-4151" }, { "affs": [ 11, 1 ], "name": "Steven Wang", "orcid": "0000-0002-5019-5024" }, { "affs": [ 2, 12 ], "name": "Bence Dániel", "orcid": "0000-0002-2410-8767" }, { "affs": [ 13, 14, 15 ], "name": "Leif S. Ludwig", "orcid": "0000-0002-2916-2164" }, { "affs": [ 16, 3 ], "name": "Brooke E. Howitt", "orcid": "0000-0002-0309-6680" }, { "affs": [ 17, 8 ], "name": "Caleb A. Lareau", "orcid": "0000-0003-4179-4807" }, { "affs": [ 18, 3, 19 ], "name": "Ansuman T. Satpathy", "orcid": "0000-0002-5167-537X" } ], "bibtex": "https://research.draconitic.com/paper/12xvq5edxmh9x.bib", "cited_by": 8, "doi": "10.1016/j.ccell.2026.05.006", "fulltext_url": null, "id": "12xvq5edxmh9x", "issns": [ "1535-6108", "1878-3686" ], "landing_url": "https://doi.org/10.1016/j.ccell.2026.05.006", "language": "en", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2403|Immune cells in cancer" ] ], "openalex": "W4412524286", "pdf_url": null, "pmcid": "PMC12330704", "pmid": "40777278", "published": "2026-06-04", "publisher": "Cell Press", "ris": "https://research.draconitic.com/paper/12xvq5edxmh9x.ris", "sources": [ { "first_seen": "2026-10-30T13:26:51Z", "native_id": "W4412524286", "source": "openalex", "url": "https://doi.org/10.1016/j.ccell.2026.05.006" } ], "subjects": [ { "field": "biology", "origin": "openalex:2403|Immune cells in cancer", "subfield": "immunology" } ], "title": "Clonal lineage tracing of innate immune cells in human cancer", "title_text": "Clonal lineage tracing of innate immune cells in human cancer", "type": "peer-reviewed", "updated_at": "2026-11-09T13:21:11Z", "url": "https://research.draconitic.com/paper/12xvq5edxmh9x", "venue": "Cancer Cell", "versions": [] }