As a promising biomarker, human epididymis protein 4 (HE4) shows wide applications for early diagnosis and therapy of ovarian cancer. Herein, heterostructured Au nanoparticles/CdS nanosheet (Au NPs/CdS NS) were initially constructed by two-step electrodeposition and used to build photoelectrochemical (PEC) and electrochemical (EC) dual-mode immunosensors for the detection of HE4. As one of appealing properties, surface Plasmon resonance (SPR) effects of Au NPs endowed the Au NPs/ CdS NS heterostructures with highly enhanced PEC and EC signals upon light irradiation, which were gradually weakened by elevating the HE4 concentrations. Under the optimal conditions, the dual-mode sensor displayed wider linear ranges of 0.01−100 and 0.01−200 ng mL −1 for PEC and EC modes, respectively. The detection limits were 1.084 and 1.188 pg mL −1 for PEC and EC detections, respectively. This sensing platform holds great potential for the analysis of other biomarkers in the clinical field.