The efficacy of charge carrier separation plays a crucial role in influencing the practical application of photoelectrochemical (PEC) detection platforms, which can be meticulously engineered to realize highly sensitive detection at the sensing interface. Hence, a novel dual-drive strategy was proposed to integrate thermally-assisted external drive behavior with the internal drive behavior of sulfur vacancies (SVs), realizing the rapid separation of charge at the S-scheme heterojunction sensing interface. On the one hand, unabsorbed solar energy was utilized an external driving force to facilitate efficient photothermoelectric conversion within the In2S3/CdS heterojunction, achieving the photocurrent response intensity 1.5 times higher than conventional PEC detection methods. On the other hand, introducing sulfur vacancies (SVs) as internal driving forces induced ordered migration and directional flow of charge carriers. Moreover, density functional theory (DFT) calculations and experimental results demonstrated that photo-generated carriers achieved rapid separation along the S-scheme heterojunction. Under the optimal conditions, a biosensor constructed based on the dual-drive strategy exhibited high sensitivity for the CD44 (cluster of differentiation-44) cluster, with a low detection limit of 0.132 pg mL−1and a wide linear range of 0.001 ∼ 1000 ng mL−1. The proposed strategy offers new insights into how to effectively harness excess energy in the traditional ultraviolet spectral range for ultrasensitive biosensors.