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Within the tumour microenvironment, CD4⁺ T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules^,, but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood. Here we performed in-depth analysis of the phenotype and tumour specificity of CD4⁺ T cells infiltrating human melanoma specimens, finding that exhausted cytotoxic CD4⁺ T cells could be directly induced by melanoma cells through recognition of HLA class II-restricted neoantigens, and also HLA class I-restricted tumour-associated antigens. CD4⁺ T regulatory (T_Reg) cells could be indirectly elicited through presentation of tumour antigens via antigen-presenting cells. Notably, numerous tumour-reactive CD4⁺ T_Reg clones were stimulated directly by HLA class II-positive melanoma and demonstrated …