Self tolerance limits immune responses to self-proteins, preventing autoimmunity and creating a significant barrier to developing cancer immunotherapeutics. Preclinical and clinical studies have revealed a novel tolerance mechanism limiting GUCY2C-specific immune responses and antitumor efficacy. Rather than eliminating all three adaptive immune lineages (CD4⁺ T, CD8⁺ T, and B lymphocytes), GUCY2C tolerance was characterized by selective CD4⁺ T cell tolerance, while CD8⁺ T and B cells were unaffected. Importantly, CD4⁺ T cells serve a critical "helper" role in immune responses, and in the absence of GUCY2C-specific CD4⁺ T cell responses, CD8⁺ T and B cell response were also inhibited. Further defining mechanism(s) underlying select CD4⁺ T cell tolerance to GUCY2C will create strategies for next-generation GUCY2C vaccines.