Self-tolerance, presumably through lineage-unbiased elimination of self antigen-specific lymphocytes (CD4+ T, CD8+ T and B cells), creates a formidable barrier to cancer immunotherapy. In contrast to this prevailing paradigm, we demonstrate that for some antigens self-tolerance reflects selective elimination of antigen-specific CD4+ T cells, but preservation of CD8+ T- and B-cell populations. In mice, antigen-specific CD4+ T-cell tolerance restricted CD8+ T- and B-cell responses targeting the endogenous self antigen guanylyl cyclase c (GUCY2C) in colorectal cancer. While selective CD4+ T-cell tolerance blocked GUCY2C-specific antitumor immunity and memory responses, it offered a unique solution to the inefficacy of GUCY2C vaccines through recruitment of self antigen-independent CD4+ T-cell help. Incorporating CD4+ T-cell epitopes from foreign antigens into vaccines against GUCY2C reconstituted CD4+ T-cell help, revealing the latent functional capacity of GUCY2C-specific CD8+ T- and B-cell pools, producing durable antitumor immunity without autoimmunity. Incorporating CD4+ T-cell epitopes from foreign antigens into vaccines targeting self antigens in melanoma (Trp2) and breast cancer (Her2) produced similar results, suggesting selective CD4+ T-cell tolerance underlies ineffective vaccination against many cancer antigens. Thus, identification of self antigens characterized by selective CD4+ T-cell tolerance and abrogation of such tolerance through self antigen-independent T-cell help is essential for future immunotherapeutics.This article is protected by copyright. All rights reserved