BACKGROUND: Overcoming immune suppression is a major barrier to eliciting potent CD8 T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4Foxp3 regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early clinical trials. However, the underlying basis for treatment efficacy, more specifically the implications of codepleting other CD4-expressing cell compartments in tumor-bearing hosts, is not well understood. METHODS: Tumor-bearing mice were treated with anti-CD4 versus other therapies that preserve helper T cell function, and the priming, tissue distribution, and maintenance of tumor antigen-specific CD8 T cells were assessed. Antibody blockade and transgenic mouse models were used to determine the mechanisms of CD8 T cell priming. Single-cell RNA-sequencing (scRNAseq) was used to further characterize CD8 T cells that are primed by anti-CD4 therapy and to identify immunosuppressive CD4 T cell subsets in human melanoma following immune checkpoint blockade (ICB). RESULTS: Comparing anti-CD4 to dual ICB therapy, we show that anti-CD4 facilitates more robust priming of TCF-1, IL-2-producing, tumor-specific CD8 T cells that disseminate to tissues and form memory. By decoupling priming from homeostatic proliferation and associated cytokines, we find that anti-CD4 functions independently of creating homeostatic space for CD8 T cells. We also show that depletion of CD4-expressing antigen-presenting cell subsets is not required for anti-CD4 efficacy. Instead, robust tumor-specific CD8 T cell priming and memory generation required the removal of total antigen-specific CD4 T cells, including both Tregs and CD4 Foxp3-negative conventional (Tconv) cells. In particular, the elimination of CD4 Tconv cells was necessary for the accumulation and maturation of conventional type-1 dendritic cells in tumor-draining LNs, which were required for CD8 T cell priming. Accordingly, anti-CD4 treatment restored CD8 T cell responses in mice cotreated with dual ICB. scRNAseq of melanoma tumors from patients who received ICB revealed the presence of Tr1 and Treg subsets, as well as CD4 Tconv subsets that lacked clear transcriptional evidence of helper differentiation. CONCLUSIONS: These findings underscore the underappreciated benefit of depleting CD4 Tconv cells to promote systemic primary and memory CD8 T cell responses against cancer.