Cancer immunotherapy, particularly immune checkpoint inhibitors (ICBs) like anti-PD-1 antibodies, has revolutionized cancer treatment. However, only a subset of patients responds to ICB therapy. Previously, we demonstrated that caerin 1.1 and 1.9, host-defence peptides from the Australian tree frog, significantly enhanced the efficacy of anti-PD-1 and therapeutic vaccines in the murine TC-1 model when administered intratumorally by activating tumour-associated macrophages. In the current study, using a murine B16 melanoma model, we find that caerin 1.1 and 1.9, combined with anti-CD47 and a therapeutic vaccine (the triple therapy, TT), inhibit the growth of both caerin-injected primary tumours and distant metastatic tumours. Tumour volumes on the treated side were significantly reduced compared to the untreated and control groups, with notable inhibition observed on Day 21 post B16 cell injection. Survival analysis indicates that mice receiving the TT exhibit significantly extended survival on both the treated and distant sides. Single-cell RNA sequencing of CD45+ cells from distant tumours reveals a significant expansion of conventional type 1 dendritic cells (cDC1s) and CD4+CD8+ T cells, along with a shift in tumour-associated macrophages towards a more immune-responsive M1 phenotype in the TT group compared to untreated or control groups.