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The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009934) and RNA (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0\u2009cm and 10.0\u2009cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single\u2010cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in\n                      <jats:italic>CD58<\/jats:italic>\n                      ,\n                      <jats:italic>STAT6<\/jats:italic>\n                      , and\n                      <jats:italic>EBF1<\/jats:italic>\n                      ; adverse genetic subtypes such as EZB\u2010like MYC\n                      <jats:sup>+<\/jats:sup>\n                      and\n                      <jats:italic>TP53<\/jats:italic>\n                      <jats:sup>Mut<\/jats:sup>\n                      ; activation of oncogenic pathways (JAK\/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with\n                      <jats:italic>CTLA\u20104<\/jats:italic>\n                      ,\n                      <jats:italic>TIGIT<\/jats:italic>\n                      ,\n                      <jats:italic>ICOS<\/jats:italic>\n                      , and\n                      <jats:italic>CD28<\/jats:italic>\n                      expression inversely correlated with tumor diameter, while\n                      <jats:italic>CD70<\/jats:italic>\n                      and\n                      <jats:italic>4\u20101BBL<\/jats:italic>\n                      expression positively correlated. Single\u2010cell RNA sequencing further revealed mutation\u2010specific tumor microenvironment insights.\n                      <jats:italic>CD58<\/jats:italic>\n                      \u2010mutated tumor exhibited a profoundly immune\u2010deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas\n                      <jats:italic>STAT6\u2010<\/jats:italic>\n                      mutated tumor was associated with increased fibroblasts and CD4\u2009+\u2009T cells, particularly regulatory T cells (Treg) and Th1\u2010like cells;\n                      <jats:italic>EBF1<\/jats:italic>\n                      \u2010mutated tumor was characterized by increased proportions of malignant B cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.72204","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T04:22:11Z","timestamp":1788754931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B\u2010Cell Lymphoma With Bulky Disease"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2932-1034","authenticated-orcid":false,"given":"Yu\u2010Qing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hematology The First Affiliated Hospital of Harbin Medical University  Harbin China"},{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics; National 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