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This study developed an HRS cell gene expression signature to identify HRS cells in single\u2010cell RNA sequencing (scRNA\u2010seq) data, investigated cognate interactions, analyzed bulk transcriptomes, and assessed predictors of treatment failure. Differentially expressed genes (DEGs) from RelB\u2010silenced U\u2010HO1 cells were identified, and scRNA\u2010seq data was processed to annotate cell types. Cognate interactions were analyzed using CellPhoneDB, and bulk transcriptome deconvolution was performed using CIBERSORT. Ridge regression models were built and evaluated. A 37\u2010gene HRS cell signature identified HRS cells (2.7%) in scRNA\u2010seq data, revealing efferocytosis pathway enrichment. Macrophages showed the highest cognate interactions, including efferocytosis\u2010related interactions with HRS cells. Bulk transcriptome analysis of 130 cHL patients showed increased M2 macrophage proportions correlated with poorer treatment response (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001). Ridge regression predicted response to treatment (RtoT) with an AUC of 0.83, identifying HRS cells and M2 macrophages as key predictors. Hierarchical clustering based on 19 genes revealed distinct RtoT outcomes, with high efferocytosis\/M2 gene expression correlating with poor response. Increased MerTK, CD209, CD14, and CD36 expression was associated with poorer outcomes. Combining gene expression and cell type proportions improved RtoT prediction (AUC 0.87). A validated HRS cell gene expression signature enabled precise HRS cell identification and accurate estimation of cell proportions. HRS cell and M2 macrophage proportions, along with efferocytosis\u2010related genes, predicted treatment failure. Efferocytosis\u2010mediated M2 macrophage polarization, controlled by HRS cells, may be a critical immune checkpoint in cHL.<\/jats:p><\/jats:sec>","DOI":"10.1002\/hon.70135","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T02:06:41Z","timestamp":1758506801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Efferocytosis and M2 Macrophage Polarization Gene Expression Correlates With Relapsed and Refractory Classical Hodgkin Lymphoma Patients: A Multi\u2010Omic Analysis"],"prefix":"10.1002","volume":"43","author":[{"given":"Juan Quarroz","family":"Braghini","sequence":"first","affiliation":[{"name":"Divisi\u00f3n Anatom\u00eda Patol\u00f3gica Facultad de Medicina Hospital de Cl\u00ednicas \u201cJos\u00e9 de San Mart\u00edn\u201d Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Cecilia","family":"Cabral Lorenzo","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n Anatom\u00eda Patol\u00f3gica Facultad de Medicina Hospital de Cl\u00ednicas \u201cJos\u00e9 de San Mart\u00edn\u201d Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Kornblihtt","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n Hematolog\u00eda Facultad de Medicina Hospital de Cl\u00ednicas \u201cJos\u00e9 de San Mart\u00edn\u201d Universidad de Buenos Aires  Buenos Aires Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana S.","family":"De Lorenzo","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Cancer Prevention Department of Cell Biology &amp; Molecular Medicine Office of Education\u2010Rutgers New Jersey Medical School  New Jersey Newark USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2172-8167","authenticated-orcid":false,"given":"Stella Maris","family":"Ranuncolo","sequence":"additional","affiliation":[{"name":"Instituto de Oncolog\u00eda \u201c\u00c1ngel H. 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