Metal-organic framework nanocrystal (Zn-MOF) was synthesized by using 3,3'-{(propane-1,3-diyl)bis[1-(4-carboxybenzyl)-1H-imidazol-3-ium]} hexafluorophosphate ionic liquid as the functional monomer and Zn as the central metal ion under hydrothermal conditions. Spatially confined gold nanoparticles (Au-NP) were prepared by in-situ reduction of chloroauric acid in the nanopores of Zn-MOF using acetic acid as the reducing agent to fabricate Au-NP@Zn-MOF nanocomposites. Au-NPs@Zn-MOF was further functionalized with 1H-imidazolium-1,3-bis(2-aminoethyl)bromide ionic liquid (IBABr) to prepare IBABr-Au@Zn-MOF nanocomposites. All abovementioned nanomaterials were thoroughly characterized by TEM, SEM, XPS, FTIR, and nitrogen-adsorption surface area analysis. IBABr-Au@Zn-MOFnanocomposites were then deposited onto a glassy carbon electrode and used as the photoactive element to fabricate a label-free photoelectrochemical (PEC) immunosensor by immobilizing anti-squamous cell carcinoma antigen (anti-SCCA). The PEC sensing principle is based on the photocurrent decline due to the blocking effect of SCCA on the electron and mass transfer after binding SCCA to anti-SCCA. The photocurrent variation related to the specific recognition of SCCA shows a linear relationship to the logarithm of SCCA concentration in the range of 5.0 pg mL to 15.0 ng mL. The detection limit is as low as 2.34 pg mL. Such a signal-off PEC immunosensor is highly selective, sensitive, stable, and reproducible towards SCCA detection. Its performance is comparable to enzyme-linked immunosorbent assay from the studies on clinical samples. This immunosensor is promising for the label-free determining SCCA in clinical human serum samples.