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Background Melanoma is one of the deadliest forms of skin cancer. Irreversible electroporation (IRE) is an innovative, non-thermal ablation technology for treating irresectable solid cancers. However, most IRE treatments are incapable of cancer eradication and only temporarily prolong patient survival. Methods In this study, we developed a novel IRE + Combo treatment regimen that combines IRE-ablation with Combo-adjuvant [CpG, anti-PD-L1 antibody (PD-L1-Ab) and CD40-agonist] and investigated its anti-tumor immunity in a mouse BL6-10 OVA (BL OVA ) melanoma model. Results We demonstrated that inclusion of the CD40-agonist in the IRE + Combo treatment regimen promoted a more robust CD8 + T cell response (6.89%) when compared with IRE + CpG/PD-L1-Ab (2.67%) or IRE alone (0.21%) treatments, leading to eradication of subcutaneous BL OVA melanoma in 5/8 of BL OVA -bearing mice and simultaneous elimination of lung melanoma metastases. Addition of CD40-agonist to the IRE + Combo treatment regimen also induced a higher frequency (17.1%) of CD8 + CD103 + conventional type-1 dendritic cells (cDC1s) with up-regulated expression of CD54, CD80, MHC II, Bcl-xL and 41BBL in tumor-drainage lymph nodes (TDLNs) relative to the control IRE + CpG/PD-L1-Ab (12.1%) and IRE alone (9.0%) treatment groups. We also show that CD40-agonist stimulated a higher frequency of CD103 + TCF1 + tissue-resident memory T (T RM ) cells (32.1%) in TDLNs when compared with the two control (15.3% and 6.7%) treatment groups, and that these T RM cells exhibited enhanced mitochondrial content and greater relative expression of the effector cytokines IFN-γ and TNF-α and the transcriptional regulators TRAF1, p38-MAPK and PGC-1α. Conclusion Taken together, this study establishes that the CD40-agonist greatly potentiates the efficacy of IRE-ablation for metastatic melanoma by promoting unexpected CD8 + CD103 + cDC1 and CD103 + TCF1 + T RM cell responses and suggests the importance of targeting CD40-signaling to improve the efficacy of cancer IRE-ablation therapy.