Circular RNAs (circRNAs) can serve as a source of neoantigens for cancer vaccines, particularly in colorectal cancer (CRC). This study investigated the potential of tumor-associated circRNAs as an alternative source of neoepitopes in CRC. Using the MiOncoCirc database and ribodepletion RNA sequencing, researchers identified circRNAs that are upregulated in CRC tumor samples. Candidate circRNAs were validated using quantitative real-time PCR (RT-qPCR) and translation prediction tools. The immunogenicity of the candidate antigens was assessed through in vitro assays and patient-derived organoids. The study found that circRAPGEF5 and circMYH9 can generate immunogenic neoepitopes that elicit CD8+ T cell responses and can specifically target and eliminate tumor-derived organoids. CircMYH9 was also detected in liquid biopsies of CRC patients, suggesting its potential as a biomarker for cancer vaccine development. The findings highlight the feasibility of tumor-associated circRNAs as an alternative source of neoantigens for cancer vaccines targeting tumors with moderate mutation levels. The study underscores the potential of circRNAs as a source of immunogenic neoantigens, offering a new avenue for cancer immunotherapy.Circular RNAs (circRNAs) can serve as a source of neoantigens for cancer vaccines, particularly in colorectal cancer (CRC). This study investigated the potential of tumor-associated circRNAs as an alternative source of neoepitopes in CRC. Using the MiOncoCirc database and ribodepletion RNA sequencing, researchers identified circRNAs that are upregulated in CRC tumor samples. Candidate circRNAs were validated using quantitative real-time PCR (RT-qPCR) and translation prediction tools. The immunogenicity of the candidate antigens was assessed through in vitro assays and patient-derived organoids. The study found that circRAPGEF5 and circMYH9 can generate immunogenic neoepitopes that elicit CD8+ T cell responses and can specifically target and eliminate tumor-derived organoids. CircMYH9 was also detected in liquid biopsies of CRC patients, suggesting its potential as a biomarker for cancer vaccine development. The findings highlight the feasibility of tumor-associated circRNAs as an alternative source of neoantigens for cancer vaccines targeting tumors with moderate mutation levels. The study underscores the potential of circRNAs as a source of immunogenic neoantigens, offering a new avenue for cancer immunotherapy.