Cytotoxic CD4⁺ T cells in cancer: Expanding the immune effector toolbox

Cytotoxic T cells are important effectors of anti-tumor immunity. While tumor killing is ascribed to CD8⁺ T cell function, pre-clinical and clinical studies have identified intra-tumoral CD4⁺ T cells that possess cytotoxic programs and can directly kill cancer cells. Cytotoxic CD4⁺ T cells are found in other disease settings including infection and autoimmunity. Here, we review the phenotypic and functional characteristics of cytotoxic CD4⁺ T cells in non-cancer and cancer contexts. We conduct a comparative examination of cytolytic mechanisms of cytotoxic CD4⁺ T cells across disease states and synthesize features that define these cells independent of context. We discuss regulatory mechanisms driving ontogeny and effector function and evidence for the clinical relevance of cytotoxic CD4⁺ T cells in cancer. In this context, we highlight important gaps in understanding in the biology of cytotoxic CD4⁺ T cells as well as the potential use of these cells in immunotherapies for specific cancers.