Indeed, when MHC-I neoepitopes are targeted with long epitope immunogens, off-target binding to MHC-II occurs, resulting in indirect CD4+ T-cell responses that drive antitumor immunity.20 Thus, while targeting CD4+ T-cell epitopes via long immunogens is a dominant strategy that provides help for CD8+ T-cell generation,21 it confounds direct induction of Ag-specific CD8+ T cells to lyse tumor cells from a pool of neoepitope candidates selected on the basis of MHC-I binding. Here, CD4 is linked to neoplasm.