Cancer immunotherapies targeting CTLA4 and or PD1/PDL1 alone or in combination have elicited remarkable clinical responses in some advanced cancers. Currently the efficacy of these immunotherapies to treat earlier stages of disease is being assessed in an adjuvant setting. We previously demonstrated in two orthotopic mouse models of spontaneously metastatic breast cancer, the significantly greater therapeutic power of neoadjuvant compared with adjuvant immunotherapies in the context of cancer surgery. Elevated and sustained peripheral tumor-specific CD8⁺ T cells after neoadjuvant immunotherapy underpinned the outcome. In this study, we have further delineated the innate immune cells and cytokines that are required for the efficacy of neoadjuvant immunotherapy. We demonstrated neoadjuvant immunotherapy in tumor-bearing Batf3 gene-targeted mice, which lack Batf3⁺ DCs resulted in a complete loss of efficacy. Similarly, blocking type I IFN, which prevents activation of Batf3⁺ DCs during neoadjuvant immunotherapy also led to a complete loss of efficacy and this was due to significantly lower levels of tumor-specific activated CD8⁺ T cells in the blood and tumors of these mice. Finally, we assessed how the scheduling and duration between neoadjuvant immunotherapies and surgery impacts on its efficacy. We demonstrated resection of the primary 4T1.2 tumor soon after neoadjuvant combination immunotherapy (anti-PD1+anti-CD137) was required for its efficacy as prolonging the duration between treatment and surgery significantly reduced overall survival. Interestingly, the addition of adjuvant combination immunotherapies following neoadjuvant immunotherapy and surgery did not further increase overall survival. In contrast, biochemical immune-related adverse events (irAEs) increased in these tumor-bearing mice compared to similar groups that only received two doses of neoadjuvant combination immunotherapy. Our data suggest that not only is a short dose of neoadjuvant combination immunotherapy sufficient to induce effective anti-tumor immunity, it may also reduce the development of severe irAEs.