The Role of FTO in the Regulation of T Cell Function and Immune Infiltration, and Its Potential Applications in Immunotherapy

The Fat Mass and Obesity-Associated Protein (FTO), a primary N6-methyladenosine (m6A) demethylase, has emerged as a critical regulator of T cell function, immune infiltration, and immunotherapy efficacy. This review synthesizes current evidence on FTO's enzymatic mechanisms, its impact on T cell differentiation and exhaustion, and its role in shaping the tumor immune microenvironment (TIME). We explore how FTO-mediated m6A demethylation modulates key transcripts involved in T cell survival , effector function, and metabolic pathways. Additionally, we examine FTO's influence on immune cell infiltration patterns across cancers, including hepatocellular carcinoma (HCC) and glioblastoma, and its contribution to immunosuppressive niches. The review highlights therapeutic strategies targeting FTO—such as small-molecule inhibitors and PROTAC degraders—and their synergistic potential with immune checkpoint inhibitors (ICIs), radiotherapy, and targeted agents. Finally, we address unresolved questions regarding FTO substrate specificity, context-dependent functions, and challenges in clinical translation, emphasizing opportunities for advancing cancer immunotherapy through epigenetic reprogramming.