The genomic and transcriptomic mutation landscapes in tumors are distinct. However, exploring tumor-specific antigens (TSAs) has been narrowly confined to exonic mutations, limiting antigen discovery, particularly in low tumor mutation burden (TMB) scenarios. Here, we unveil the broader spectrum of TSAs by employing an integrative proteogenomic strategy that synergizes whole-genome sequencing, transcriptomic analysis, and MHC class I immunoprecipitation coupled with mass spectrometry (IP-MS). Analyzing ten paired primary colorectal cancer (CRC) specimens with diverse TMBs, we discovered 171 unique TSAs with no shared epitopes across patients, revealing a dominant genomic origin (86.55%) for these antigens. Intriguingly, we discovered that a significant majority (84.79%) of TSAs emanate from non-coding regions, with intergenic mutations alone contributing to 34.50% of the TSA pool. These intergenic TSAs were notably more prevalent in hypermutated CRCs, presenting nearly 40-fold more antigens than their non-hypermutated counterparts. We further validated the immunogenicity of these novel intergenic TSAs, marking them as promising candidates for expanding the neoantigen repertoire in immunotherapy. Our findings challenge the current neoantigen discovery paradigm and propose a new, untapped reservoir of immune epitopes poised to revolutionize the selection of targets for cancer immunotherapy.