Single-atom nanozymes (SAzymes), with individually isolated metal atom as active sites, have shown tremendous potential as enzyme-based drugs for enzymatic therapy. However, using SAzymes in tumor theranostics remains challenging because of deficient enzymatic activity and insufficient endogenous HO. We develop an external-field-enhanced catalysis by an atom-level engineered FeN-centered nanozyme (FeN-SAzyme) for radio-enzymatic therapy. This FeN-SAzyme exhibits peroxidase-like activity capable of catalyzing HO into hydroxyl radicals and converting single-site Fe species to Fe for subsequent glutathione oxidase-like activity. Density functional theory calculations are used to rationalize the origin of the single-site self-cascade enzymatic activity. Importantly, using X-rays can improve the overall single-site cascade enzymatic reaction process via promoting the conversion frequency of Fe/Fe. As a HO producer, natural glucose oxidase is further decorated onto the surface of FeN-SAzyme to yield the final construct GOD@FeN-SAzyme. The resulting GOD@FeN-SAzyme not only supplies in situ HO to continuously produce highly toxic hydroxyl radicals but also induces the localized deposition of radiation dose, subsequently inducing intensive apoptosis and ferroptosis in vitro. Such a synergistic effect of radiotherapy and self-cascade enzymatic therapy allows for improved tumor growth inhibition with minimal side effects in vivo. Collectively, this work demonstrates the introduction of external fields to enhance enzyme-like performance of nanozymes without changing their properties and highlights a robust therapeutic capable of self-supplying HO and amplifying self-cascade reactions to address the limitations of enzymatic treatment.