TDG (thymine DNA glycosylase) is a DNA repair enzyme that plays crucial roles in both base excision repair and active DNA demethylation. As a DNA glycosylase, TDG specifically recognizes and excises 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from CpG sites, facilitating active DNA demethylation through the base excision repair pathway 1. This demethylation process involves TET dioxygenase-mediated oxidation of 5-methylcytosine to intermediate forms, followed by TDG-dependent excision and repair to restore unmethylated cytosine 1. TDG also functions in traditional DNA repair by correcting G/T mispairs that arise from spontaneous deamination of 5-methylcytosine to thymine, though this role is secondary to its demethylation function. The enzyme generates endogenous single-strand breaks during active demethylation, particularly in neurons where it targets enhancer regions 2. Beyond DNA repair, TDG has emerging roles in gene regulation and cellular signaling. Recent research demonstrates that TDG mediates pro-tumor macrophage polarization through DNA demethylation regulated by p53 signaling, contributing to immune evasion in breast cancer 3. TDG activity can be exploited therapeutically, as disruption of its gap-filling process triggers DNA damage responses that can be leveraged in cancer treatment strategies 2.