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Patients with CLL have immune\u2010related abnormalities in T lymphocyte subset composition, immune synapse formation, and other immune dysregulations. Cellular interactions between the disease clone and its microenvironment provide therapeutic opportunities to target these tumor pathogenesis pathways, potentially improving the patient's immune functions and clinical outcomes of targeted therapies. At present, despite the lack of response of immune checkpoint inhibitors in CLL, they showed promising efficacy in patients with Richter transformation. Together with CD19\u2010targeted chimeric antigen receptor\u2013modified T cell (CAR\u2010T) therapy, novel bispecific antibodies and other immunotherapies are being investigated to improve survival outcomes for patients with relapsed or refractory (R\/R) CLL, as exemplified by epcoritamab, a bispecific antibody that recently demonstrated initial efficacy in R\/R CLL and in patients in high\u2010risk CLL subgroups, including those with\n                    <jats:italic>TP53<\/jats:italic>\n                    aberrations and unmutated genes that encode immunoglobulin variable heavy chain region (\n                    <jats:italic>IGHV<\/jats:italic>\n                    ). Furthermore, to address the immune escape of cancer cells and issues that impact the durability of single\u2010targeted T cell\u2010redirected therapies, novel strategies such as trispecific antibodies and combination therapies are being investigated to increase tumor specificity or immune cell activation. In summary, there is emerging evidence that immunotherapies may counteract the immunosuppressive microenvironment of CLL, improve clinical responses, decrease the risk of infection, and overcome treatment resistance.\n                  <\/jats:p>","DOI":"10.1111\/ejh.14408","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T11:33:30Z","timestamp":1741692810000},"page":"953-972","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the Immune Microenvironment in Chronic Lymphocytic Leukemia: An Evolving Therapeutic Strategy"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7189-6612","authenticated-orcid":false,"given":"Clement","family":"Chung","sequence":"first","affiliation":[{"name":"Houston Methodist West Hospital  Houston 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