Efficient signal amplification strategies are crucial for ultrasensitive detection of tumor markers. Herein, a new signal amplification strategy by coupling cascade catalysis-initiated radical polymerization with impedimetric immunoassay was proposed for ultrasensitive detection of carbohydrate antigen 15-3 (CA15-3). Copper-based metal-organic framework nanoparticles (Cu-MOF), as peroxidase mimics, combined with CA15-3 antibody (Ab2) and glucose oxidase (GOx) were employed as immunoprobes to initiate radical polymerization by cascade catalysis. In this work, the oxidation of glucose was catalyzed by GOx to generate hydrogen peroxide (H2O2), which reacted with acetylacetone (ACAC) via Cu-MOF catalysis to yield ACAC radicals for the polymerization of N-isopropylacrylamide (NIPAM). The polymer, poly (N-isopropylacrylamide) (PNIPAM), was generated in situ from the radical polymerization. As resistance enhancer, PNIPAM was covered on electrode surface to amplify resistance value by its poor conductivity. With the help of polymerization-based amplification, the resistance differences caused by target were improved significantly. Under optimum conditions, the designed biosensor showed wide detection ranges from 10 μU/mL to 10 mU/mL and 10 mU/mL to 100 U/mL, with ultralow detection limit of 5.06 μU/mL for CA15-3. Such an approach opened a new avenue for signal amplification, thus offering an ultrasensitive detection platform for a broad range of tumor markers.