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Abstract
CD4 T cells play complex roles in cancer immunotherapy, acting as both enhancers and suppressors of anti-tumor immunity. This study examined tumor-specific CD4 T cells in adoptive immunotherapy and their interaction with CD8 T cells in melanoma-bearing lymphopenic mice. Co-transfer of CD4 and CD8 T cells improved therapeutic efficacy, sustained effector CD8 phenotypes, and reduced exhaustion markers compared to CD8-only treatment. Additional experiments in a multi-vaccination model showed that partial CD4 depletion reduced regulatory T cell expansion and enhanced tumor protection. Findings underscore the dual nature of CD4 T cells and highlight strategies to optimize their use in cancer immunotherapy.