Background <p>Genomic alterations can drive tumorigenesis, and understanding the immune response to those alterations may aid in developing new targets for diagnosis and therapy. Tumour-associated antigens (TAAs) are self-antigens that are abnormally expressed in tumours. Autoantibodies (AAbs) triggered by TAAs have been considered reporters of early carcinogenesis. This study aimed to profile AAbs to overexpressed or driver gene-related proteins (DRPs) in prostate cancer (PCa).</p> Methods <p>Twenty-nine targets including 14 overexpressed proteins and 15 DRPs were screened via serological proteome analysis and bioinformatics analysis, respectively. ELISA was then performed to assess their corresponding AAbs in 293 serum samples. Immunohistochemistry (IHC) was used to determine the tissue expression of TAAs.</p> Results <p>Nineteen AAbs showed significantly higher serum levels in PCa patients than in normal controls. A panel with four AAbs (PIK3CA, SPOP, IF4H, HSP60) was developed, showing an AUC of 0.901. A differential AAb response to these four TAAs was observed in three distinct PCa populations. The panel was evaluated across six other common cancers including 445 serum samples, showing potential for multi-cancer detection. High expression of the four TAAs targeted by AAbs was found in PCa tissues by IHC.</p> Conclusions <p>These findings suggest that overexpressed proteins or DRPs may have altered immunogenicity, leading to the production of corresponding AAbs.</p>