A major reason that T cell-based melanoma immunotherapies can fail, either initially or after a period of treatment, is due to mutations that result in CD8+ T cells being incapable of directly recognizing and killing tumor cells. Many melanomas, however, express HLA-II which enables tumor cells to be recognized and eliminated by an alternative lymphocyte subset called CD4+ T cells. Unlike tumor cell killing by CD8+ T cells, the molecular mechanisms governing response and resistance of tumor cells to CD4+ T cell killing have previously not been studied in a systematic and unbiased fashion. This gap in knowledge limits the rational application of CD4+ T cells as an effector population in melanoma immunotherapies. Using a genome-scale CRISPR screen I recently identified genes that confer enhanced sensitivity or resistance of melanoma cells to CD4+ cell killing. I discovered that loss of function of the RNA-binding protein PCBP2 led to enhanced killing of tumor cells by CD4+ T cells. The tumor-intrinsic role of PCBP2 in tumor immunology has previously not been studied. In my project, I seek to define the molecular mechanisms that control enhanced tumor-intrinsic sensitivity of PCBP2-deleted melanoma cells to immunologic attack by CD4+ T cells. These findings will inform a novel, mechanism-based immunotherapeutic approach that augments antitumor efficacy of CD4+ T cells in melanoma and other common cancers.