Epi‐Immunotherapy in Cancer Treatment: Mechanisms, Clinical Progress, and Future Directions

Cancer immunotherapy is a groundbreaking therapeutic strategy, yet it continues to face significant challenges, including limited overall response rates and treatment resistance. Emerging research has demonstrated the pivotal role of epigenetic modifications in tumor immune evasion, providing a strong rationale for developing “epi‐immunotherapy”—an 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‐immunotherapy demonstrates a remarkable ability to enhance treatment efficacy and reverse therapeutic resistance. We also summarize the current clinical applications of epi‐immunotherapy in both hematological malignancies and solid tumors, with particular emphasis on its mechanisms for overcoming immune checkpoint inhibitor resistance and converting immunologically “cold” tumors into “hot” tumors. Despite its promising potential, epi‐immunotherapy faces several challenges that require urgent resolution. This review provides an in‐depth 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‐immunotherapy is poised to become an essential component of cancer treatment, offering patients more effective and personalized therapeutic options.