Reactive oxygen species (ROS)-catalytic therapies have gained increasing popularity in preventing tumor metastasis and recurrence, yet their efficiency is often compromised by limited systemic immune activation. Herein, we report the de novo design of Ru-coordinated bis-Schiff base salphen-covalent organic frameworks (SCOF-Ru) to serve as semiconducting artificial enzymes with radio-activable ROS-catalytic efficiency and antitumor immunity for suppressing tumor metastasis and recurrence. Experimental and theoretical results demonstrate that the semiconducting SCOF-Ru displays large π-conjugation, efficient electron transfer, strong electron–hole separation, and unique Ru2–N4O2 catalytic centers, enabling the most superior ROS production capability under low-dose X-ray irradiation. Rather than relying on high-Z elements, semiconducting SCOF-Ru with optimized band structures endows Ru sites with high radiosensitization effects. Our findings have disclosed that the SCOF-Ru can not only effectively inhibit DNA repair but also trigger robust apoptosis through the downregulation of calcium signaling pathways. Correspondingly, the therapeutic superiority and recurrence inhibition efficacies of SCOF-Ru have been validated in different tumor models, especially radiotherapy-resistant patient-derived xenograft models. Combined with immune checkpoint blockade, radio-activable SCOF-Ru shows great potential to robustly inhibit the growth of distant tumors. We believe the innovative design of ROS-catalytic and radio-activable artificial enzymes will enable a promising avenue for treating malignant tumors.