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Emerging research has demonstrated the pivotal role of epigenetic modifications in tumor immune evasion, providing a strong rationale for developing \u201cepi\u2010immunotherapy\u201d\u2014an innovative approach that combines epigenetic therapy with immunotherapy. This comprehensive review systematically examines how epigenetic regulation mediates tumor immune escape and the mechanisms involved, including suppression of tumor antigen expression and antigen presentation, upregulation of immune checkpoint molecules, inhibition of antitumor immune cell recruitment and function, and enhancement of immunosuppressive cell proliferation and activity. By integrating epigenetic modulation with immunotherapeutic strategies, epi\u2010immunotherapy demonstrates a remarkable ability to enhance treatment efficacy and reverse therapeutic resistance. We also summarize the current clinical applications of epi\u2010immunotherapy in both hematological malignancies and solid tumors, with particular emphasis on its mechanisms for overcoming immune checkpoint inhibitor resistance and converting immunologically \u201ccold\u201d tumors into \u201chot\u201d tumors. Despite its promising potential, epi\u2010immunotherapy faces several challenges that require urgent resolution. This review provides an in\u2010depth analysis of these limitations, which include the complexity of epigenetic regulation, a lack of reliable biomarkers, and constraints in drug development. As our understanding of epigenetic mechanisms deepens and technologies continue to advance, epi\u2010immunotherapy is poised to become an essential component of cancer treatment, offering patients more effective and personalized therapeutic options.<\/jats:p>","DOI":"10.1002\/cai2.70023","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T03:46:02Z","timestamp":1758771962000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Epi\u2010Immunotherapy in Cancer Treatment: Mechanisms, Clinical Progress, and Future Directions"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8587-2639","authenticated-orcid":false,"given":"Nannan","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Bio\u2010therapeutic, the First Medical Centre Chinese PLA General Hospital Beijing China"},{"name":"Department of Bio\u2010therapeutic, the Fifth Medical 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