In this work, an antigen-down photoelectrochemical (PEC) immunosensor based on a signal polarity switching strategy for the detection of cytokeratin 19 fragment 21-1 (CYFRA21-1) was proposed. 3,4,9,10-Perylene tetracarboxylic acid (PTCA) is a conjugated organic dye containing five benzene nuclei, which has excellent film-forming and optical properties. PTCA sensitized by SnS2 can further improve the basal signal and the stability of the PEC immunosensor. Moreover, avidin-functionalized CuInS2 as a signal probe can convert the basal anodic photocurrent to a cathodic photocurrent. Therefore, the PEC sensor realized the photocurrent polarity conversion before and after labeling. With avidin-functionalized CuInS2, the polarity of the photocurrent was changed once CYFRA21-1 was detected. Therefore, the PEC immunosensor owns high sensitivity. The linear range of the immunosensor for the detection of CYFRA21-1 is 0.00001-500 ng·mL-1, and the detection limit is 3.5 fg·mL-1. The PEC immunosensor has good stability, high selectivity, and good repeatability. This work may provide a new way for the detection of CYFRA21-1 and other proteins.