High　entropy　(HE)　compounds　with　chemically　disordered　multi-cation　structures　have　become　a　hot　research　topic　because　of　their　fascinating　＇cocktail　effect＇.　However,　high　entropy　effect　with　the　efficient　photoelectric　response　has　not　been　reported　for　photoelectrochemical　(PEC)　immunoassays.　Herein,　an　innovative　PEC　immunoassay　for　the　sensitive　detection　of　prostate-specific　antigen　(PSA)　was　ingeniously　constructed　using　hollow　nanocubic　(ZnCdFeMnCu)xS　photoactive　matrices　with　high　entropic　effect　via　the　cation　exchange.　Initially,　a　sandwich-type　immunoreaction　has　behaved　using　dopamine-loaded　liposome　labeled　with　anti-PSA　secondary　antibodies.　In　the　presence　of　PSA,　addition　of　Triton　X-100　caused　the　liposomal　cleavage　to　release　dopamine,　which　was　then　detected　as　a　reduced　photocurrent　on　(ZnCdFeMnCu)xS-based　photoelectrode.　Under　optimal　condition,　the　PEC　immunoassay　showed　good　photocurrent　responses　toward　target　PSA　with　the　dynamic　linear　range　of　0.1–50　ng　mL−1　with　a　limit　of　detection　of　34.1　pg　mL−1.　Significantly,　this　system　can　provide　a　new　platform　for　the　development　of　PEC　immunoassays　by　coupling　with　high-entropy　photoactive　materials.　©　2023　Elsevier　B.V.