Both CD8+ and CD4+ neoantigen-specific TCR αβ responses in hard-to-treat cancers such as glioblastoma (14, 72), pancreatic malignancies (18), non-small-cell lung cancer (2, 3), melanoma (69, 76), bile duct (40) and colorectal cancers (41) are now regarded as vital to promote durable clinical responses in patients, further to the presence of suitable neoepitope restricting HLA elements (27, 223). Here, CD4 is linked to cancer.