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This study investigated potential molecular markers, the immune cell composition within the TME, and their associations with clinical outcomes in patients with primary intestinal DLBCL (PI\u2010DLBCL). We initially analyzed RNA expression in tumor cells from 19 patients with PI\u2010DLBCL in the experimental cohort. Candidate biomarkers were then assessed in lymphoma tissue from a total of 48 patients in the same cohort, including the 19 with RNA\u2010expression data, and validated in an independent cohort of 29 patients with PI\u2010DLBCL. Associations between these markers and clinicopathological features, event\u2010free survival (EFS), and overall survival (OS) in the two cohorts were analyzed. In the RNA expression panel, CCL5 expression was higher in patients with advanced\u2010stage PI\u2010DLBCL and was associated with inferior EFS and OS. Its principal receptor, CCR5, expressed in approximately one\u2010third of patients, was associated with lower complete response rates to first\u2010line immunochemotherapy: 50% in the experimental cohort and 10% in the validation cohort and correlated with the 7\u2010year worse OS rate in both the experimental (49.8% versus 71.4%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.082) and validation (0% versus 76.2%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) cohorts. In both the experimental and validation cohorts, CCR5\u2010positive tumors exhibited decreased CD86\u2010positive (M1\u2010like) and increased CD206\u2010positive (M2\u2010like) macrophage infiltration, consistent with an immunosuppressive TME. Multivariate analyses revealed that CCR5 expression was independently associated with worse EFS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) and OS (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.004) in patients with PI\u2010DLBCL (combined experimental and validation cohorts). CCR5 expression indicates a biologically aggressive subtype of PI\u2010DLBCL with poor clinical outcomes and M2 macrophage\u2013dominant immunosuppression.\n                  <\/jats:p>","DOI":"10.1002\/2056-4538.70112","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T03:27:33Z","timestamp":1786505253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Increased\n                    <scp>CCR5<\/scp>\n                    expression in lymphoma cells and\n                    <scp>M2<\/scp>\n                    macrophages is associated with poor prognosis in primary intestinal diffuse large B\u2010cell lymphoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Wei\u2010Li","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Oncology National Taiwan University Hospital and National Taiwan University College of Medicine  Taipei Taiwan"},{"name":"Graduate Institute of Oncology National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai\u2010Yun","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine National Cheng Kung University Hospital  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010An","family":"Fu","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine National Cheng Kung University Hospital  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u2010Pai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology National Taiwan University Hospital, Yunlin Branch  Douliu Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yao","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine National Taiwan University Hospital and National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiu\u2010Po","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine National Taiwan University Hospital and National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Been\u2010Ren","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Surgery National Taiwan University Hospital and National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5042-0503","authenticated-orcid":false,"given":"Chung\u2010Wu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pathology National Taiwan University Hospital and National Taiwan University College of Medicine  Taipei Taiwan"},{"name":"Department of Pathology and Laboratory Medicine Koo Foundation Sun Yat\u2010Sen Cancer Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia\u2010Lang","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Medical Research National Taiwan University Hospital and National Taiwan University College of Medicine  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung\u2010Yu","family":"Huang","sequence":"additional","affiliation":[{"name":"Medical Informatics Division ACT Genomics Co. 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