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It has long been thought that the role of CD4+T cells in the tumor microenvironment (TME) was limited to coordinating the immune response by stimulating other immune cells and by secretion of cytokines with antitumor activity, while direct killing of tumor cells has been largely attributed to cytotoxic CD8+T cells. Notably, CD4+T cells with direct cytotoxic activity (CD4+CTLs) have been reported in the context of viral infections, autoimmune disorders, and more recently in patients with various cancer types. These cells have the ability to secrete cytotoxic molecules and kill target cells in a major histocompatibility complex (MHC) class II-dependent manner. In this review, we give an overview of phenotypical characteristics of CD4+CTLs in human cancers and the antitumor mechanisms employed by these cells. Further, we explore their role and clinical relevance in the context of cancer and describe how these cells may be used for the development of novel immunotherapeutic options to benefit patients with cancer with MHC class II-positive tumors.<\/jats:p>","DOI":"10.1136\/jitc-2025-013461","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:00:27Z","timestamp":1766487627000},"page":"e013461","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Cytotoxic CD4+ T cells in cancer: an emerging target for next-generation anticancer immunotherapy?"],"prefix":"10.1136","volume":"13","author":[{"given":"Imke M B","family":"van Wandeloo","sequence":"first","affiliation":[{"name":"Medical Oncology, Radboudumc, Nijmegen, Gelderland, The Netherlands"},{"name":"Medical BioSciences, Radboudumc, Nijmegen, Gelderland, The 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