Detecting preinvasive tumors before the onset of advanced clinical symptoms represents a critical advancement in improving the efficacy of early medical interventions and reducing cancer-related mortality rates. Immunosensors have emerged as the preferred choice for analyzing oncomarkers and meeting the everincreasing demands of medical diagnostics. Therefore, the quest for the development of highly specific and sensitive immunosensors remains most sought-after to open new avenues for personalized healthcare and medical monitoring. Here, we report amplification-free and nonlabeled DNA framework-coupled AuNPs@CuMOF for ultrasensitive and highly specific electrochemical detection of carcinoembryonic antigen (CEA). Upon the CEA concentration variation from 0.0001 to 200 ng mL −1 , the proposed biosensor led to a limit of detection (LOD) of 0.25 pg mL −1 , surpassing most previously published CEA biosensors that rely on amplification-free methods and aligns with those based on amplification techniques. Furthermore, the suggested CEA immunosensor demonstrated auspiciously high specificity and sensitivity in detecting CEA in human serum comparable to the commercial ELISA within a relative error falling between 6.25% and 2.26%. The proposed analytical approach, hinging on the synergy effect of the CuMOF's large surface area and the mechanical rigidity of the three-dimensional tetrahedron DNA structured probes (3D TDNA), obviously broadens the potential of immunosensors, offering higher sensitivity and lower LOD. Therefore, this work is not only an expansion of CuMOF exploitation in electrochemical biosensing but also a major milestone in detecting diverse biomarkers in clinical settings for tumor diagnosis.