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Background Nanosecond pulsed electric field (nsPEF) ablation has demonstrated limited and transient efficacy in suppressing tumor progression. Oncolytic peptide LTX-315 is known to elicit a strong antitumor immune response and durable immune memory. This study aimed to investigate whether LTX-315 could enhance nsPEF-induced antitumor immunity in liver cancer.Methods Both cell assays and mouse models were used to evaluate the therapeutic efficacy of nsPEF, LTX-315, and combination therapy. Flow cytometry and immunofluorescence were performed to assess the tumor immune microenvironment. Co-culture models were established to evaluate the functional modulation of immune cells.Results nsPEF upregulated the programmed cell death 1 ligand 1 (PD-L1) expression in liver cancer cells, leading to CD8 + T-cell dysfunction. LTX-315 reduced the nsPEF-mediated elevated PD-L1 level and restored the cytotoxicity of CD8+ T cells. Furthermore, LTX-315 acted with nsPEF to induce enhanced immunogenic cell death for the activation of dendritic cells and CD8+ T cells. In addition, LTX-315 improved antigen processing and presentation in nsPEF-treated liver cancer cells. Notably, the combination of nsPEF and LTX-315 achieved durable tumor control and prolonged survival of the tumor-bearing mice, by promoting the migration of dendritic cells to tumor-draining lymph nodes, the infiltration of immune cells within the tumor and potential immune memory to prevent tumor metastasis.Conclusions LTX-315 functions as an immune stimulant to improve the antitumor efficacy of nsPEF. The combination of nsPEF and LTX-315 represents a promising interventional immunotherapy strategy for liver cancer.Key points LTX-315; Antitumor immune response; nsPEF; Liver cancer.