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To address how endometriosis\u2010constituting cells are different from normal endometrium and among endometriosis subtypes and how their molecular signatures are related to phenotypic manifestations, we analyzed ovarian endometrial cyst (OEC), superficial peritoneal endometriosis (SPE), and deep infiltrating endometriosis (DIE) from 12 patients using single\u2010cell RNA\u2010sequencing (scRNA\u2010seq). We identified 11 cell clusters, including EEEC, EESC, fibroblasts, inflammatory\/immune, endothelial, mesothelial, and Schwann cells. For hormonal signatures, EESCs, but not EEECs, showed high estrogen signatures (estrogen response scores and\n                    <jats:italic>HOXA<\/jats:italic>\n                    downregulation) and low progesterone signatures (\n                    <jats:italic>DKK1<\/jats:italic>\n                    downregulation) compared to normal endometrium. In EEECs, we found\n                    <jats:italic>MUC5B<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    <jats:italic>TFF3<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>low<\/jats:italic>\n                    <\/jats:sup>\n                    cells enriched in endometriosis. In lymphoid cells, evidence for both immune activation (high cytotoxicity in NK) and exhaustion (high checkpoint genes in NKT and cytotoxic T) was identified in endometriosis. Signatures and subpopulations of macrophages were remarkably different among endometriosis subtypes with increased monocyte\u2010derived macrophages and\n                    <jats:italic>IL1B<\/jats:italic>\n                    expression in DIE. The scRNA\u2010seq predicted\n                    <jats:italic>NRG1<\/jats:italic>\n                    (macrophage)\u2010\n                    <jats:italic>ERBB3<\/jats:italic>\n                    (Schwann cell) interaction in endometriosis, expressions of which were validated by immunohistochemistry. Myofibroblast subpopulations differed according to the location (OECs from fibroblasts and SPE\/DIEs from mesothelial cells and fibroblasts). Endometriosis endothelial cells displayed proinflammation, angiogenesis, and leaky permeability signatures that were enhanced in DIE. Collectively, our study revealed that (1) many cell types\u2014endometrial, lymphoid, macrophage, fibroblast, and endothelial cells\u2014are altered in endometriosis; (2) endometriosis cells show estrogen responsiveness, immunologic cytotoxicity and exhaustion, and proinflammation signatures that are different in endometriosis subtypes; and (3) novel endometriosis\u2010specific findings of\n                    <jats:italic>MUC5B<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    EEECs, mesothelial cell\u2010derived myofibroblasts, and\n                    <jats:italic>NRG1\u2010ERBB3<\/jats:italic>\n                    interaction may underlie the pathogenesis of endometriosis. Our results may help extend pathologic insights, dissect aggressive diseases, and discover therapeutic targets in endometriosis. \u00a9 2023 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6178","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T08:13:54Z","timestamp":1694160834000},"page":"323-334","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Single\u2010cell profiling identifies distinct hormonal, immunologic, and inflammatory signatures of endometriosis\u2010constituting cells"],"prefix":"10.1002","volume":"261","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2146-4336","authenticated-orcid":false,"given":"Sun","family":"Shin","sequence":"first","affiliation":[{"name":"Departments of Microbiology The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Departments of Precision Medicine Research Center\/IRCGP The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Cancer Evolution Research Center, College of Medicine The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8186-6230","authenticated-orcid":false,"given":"Youn\u2010Jee","family":"Chung","sequence":"additional","affiliation":[{"name":"Departments of Obstetrics and Gynecology The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5913-2030","authenticated-orcid":false,"given":"Seong Won","family":"Moon","sequence":"additional","affiliation":[{"name":"Cancer Evolution Research Center, College of Medicine The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Departments of Pathology The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3801-4013","authenticated-orcid":false,"given":"Eun Ji","family":"Choi","sequence":"additional","affiliation":[{"name":"Cancer Evolution Research Center, College of Medicine The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Departments of Pathology The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4492-0768","authenticated-orcid":false,"given":"Mee\u2010Ran","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Obstetrics and Gynecology The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6943-5948","authenticated-orcid":false,"given":"Yeun\u2010Jun","family":"Chung","sequence":"additional","affiliation":[{"name":"Departments of Microbiology The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Departments of Precision Medicine Research Center\/IRCGP The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Cancer Evolution Research Center, College of Medicine The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Departments of Biomedicine &amp; Health Sciences The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6677-0487","authenticated-orcid":false,"given":"Sug Hyung","family":"Lee","sequence":"additional","affiliation":[{"name":"Cancer Evolution Research Center, College of Medicine The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Departments of Pathology The Catholic University of Korea  Seoul Republic of Korea"},{"name":"Departments of Biomedicine &amp; Health Sciences The Catholic University of Korea  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0008-5"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1810764"},{"key":"e_1_2_8_4_1","first-page":"10","article-title":"How old is endometriosis? 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