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The dynamic interplay between cancer cells and the immune microenvironment shapes the balance between immune activation and evasion. Developing molecular strategies to enhance the immunogenicity of cancer cells or the effector functions of immune cells has become a major research focus for effective cancer immunotherapy. Evidence suggests that epigenetic regulation is a key mechanism modulating interactions between cancer and immune cells. However, how perturbing epigenetic landscapes in cancer or immune cells can translate into clinically applicable immunotherapeutic strategies has yet to be fully explored. Through quantitative profiling of the surface proteomes of cancer cells, we discovered that epigenetic drugs can modify immune synapticcytoskeletal networks in cancer cells, making them more susceptible to γδ T cells. These unique T cells have the ability to kill cancer cells in an MHC-unrestricted manner, making them suitable for both auto- and allogeneic adoptive cellular immunotherapy. We also developed a highly effective clinical-grade ex vivo expansion protocol for γδ T cells and identified an immune-sensitive gene signature to aid in patient selection for the clinical implementation of epigenetically facilitated γδ T cell immunotherapy in cancer. Moreover, we identified several classes of epigenetic drugs, particularly those targeting histone modifiers, that could alter T cell plasticity, reinvigorating terminally exhausted T cells for enhanced anti-tumor immunity. This reprogramming of T cell states reflects a connection between epigenetic and metabolic processes, specifically through the activation of the polyamine biosynthetic pathway and increased intracellular polyamine levels. These findings indicate a practical approach to metabolic modulation through epigenetic perturbation. In addition to shaping tumor-immune interactions, epigenetic mechanisms also play a fundamental role in delineating the immune macroenvironment in cancer patients. Our genome-wide DNA methylation analyses of circulating T cells in patients with localized early-stage lung cancer revealed subtle yet distinctive changes in the epigenetic landscapes of systemic T cells even before cancer metastasizes. These findings highlight the clinical potential of immune-related biomarkers for early cancer diagnosis. In summary, the multifaceted role of epigenetic regulation not only alters the immunogenicity of cancer cells but also serves as a nexus connecting the metabolic and functional states of immune cells in the tumor immune microenvironment. Understanding these interconnections can facilitate the development of novel diagnostic and therapeutic strategies in cancer management.