This　work　developed　a　double　ion-exchange　reaction-based　photoelectrochemical　(PEC)　immunoassay　with　the　split-type　detection　mode　for　sensitive　detection　of　prostate-specific　antigen　(PSA,　used　as　a　model).　The　nanocomposite　of　cadmium　sulfide　and　nickel　sulfide　(CdS@NiS　nanocomposite),　as　the　photoactive　material,　was　rapidly　synthesized　by　two-step　hydrothermal　treatment.　In　the　presence　of　target　PSA,　the　cupric　oxide　nanoparticle　(CuO　NP)　labeled　detection　antibody　was　introduced　into　the　detection　system　by　sandwich　immunoreaction　and　the　copper　(Cu2+)　ions　was　released　from　CuO　nanoparticles　by　acid　to　participate　in　double　ion-exchange　reaction.　The　double　ion-exchange　reaction　on　the　photoelectric　sensing　interface　between　Cu2+　and　CdS@NiS　nanocomposites　formed　the　weak　photoactive　material　CuxS　(x　=　1,　2)　to　reduce　the　photocurrent.　Under　optimal　conditions,　the　double　ion-exchange　reaction-based　PEC　immunoassay　exhibited　good　photocurrent　responses　toward　target　PSA　within　the　dynamic　working　range　from　0.01　ng　mL(-1)　to　50　ng　mL(-1)　at　a　low　limit　of　detection　(LOD)　of　2.9　pg　mL(-1).　Besides,　our　work　could　achieve　good　reproducibility　and　high　specificity　under　the　split-type　detection　mode.　Compared　with　human　PSA　ELISA　kit,　the　accuracy　obtained　by　our　strategy　was　satisfactory.　Importantly,　this　Cu2+-activated　double　ion-exchange　reaction-based　PEC　immunoassay　provides　a　promising　platform　for　the　detection　of　biomarkers.　(C)　2021　Elsevier　B.V.　All　rights　reserved.