Designing a universal route for rational synthesis of a family of hollow multinary chalcogenide semiconductors for photoelectrochemical biosensors is still facing to the enormous challenges ahead. Herein a template-assisted Cu2O surface vulcanization and etching through a Pearson’s hard and soft acid-base (HSAB) principle was utilized to synthesize hollow Cu2-xS photoactive materials for photocurrent detection of prostate-specific antigen (PSA). We initially synthesized cubic Cu2O and further surface sulfidation and HCl etching to obtain cubic Cu2-xS. Inspiringly, stirring of CuS, phosphine (TBP: tributylphosphine) and other metal salts could replace Cu+ ions to obtain new metal sulfides without changing the framework, size and thickness of the original material. This interesting phenomenon could be explained by HSAB theory, which soft base was favorable for combining soft acid (Cu+) to drive Cu+ out of the framework. Based on the results, HSAB-based reaction system was applied to develop novel photoelectrochemical PSA immunoassay. Polymetallic-doped sulfides (ZnxCd1-xS) had better photocurrent response than pure binary sulfides. Such excellent photoelectric conversion materials could sensitively detect target PSA with a wide linear range from 1.0 pg/mL to 10 ng/mL at a limit of detection down to 0.32 pg/mL. Importantly, the concept of cation exchange reaction can be widely used to synthesize advanced nanomaterials for fabrication of high-efficiency biosensing systems.