双极脉冲电场消融在同基因PDAC模型中触发局部和远隔肿瘤控制并伴随强劲的免疫激活

Pulsed Field Ablation (PFA) is a novel, non-thermal ablation modality that delivers ultrashort, high-voltage electric pulses to induce irreversible electroporation and selective tumor cell death while preserving surrounding vasculature and extracellular matrix. Although PFA has shown promise in other solid tumors, its efficacy and immunologic effects in pancreatic ductal adenocarcinoma (PDAC) remain unexplored. We evaluated a novel PFA probe and system (ALPFA Medical) in a syngeneic KPC-derived PDAC model. Tumor cells derived from genetically engineered Kras G12D ; Trp53 R172H /+; Pdx1:Cre (KPC) mice were implanted subcutaneously into immunocompetent C57BL/6 hosts. Once established, mice received PFA (n=28) or sham treatment (n=25; probe insertion without pulse delivery). Contralateral tumors were left untreated to assess systemic effects. Tumor growth, histopathology, necrosis, CD8⁺ and Granzyme B infiltration, and serum cytokine profiles were assessed at days 3, 7, and 11 post-treatment. PFA significantly inhibited growth of treated tumors versus sham controls (p=0.03). Remarkably, untreated contralateral tumors also exhibited suppressed growth (p=0.02), consistent with an abscopal immune effect. Histologic analysis showed extensive necrosis in PFA-treated tumors that progressed through day 11, with increased necrosis also evident in contralateral sites. PFA induced marked CD8⁺ T-cell infiltration and elevated Granzyme B expression peaking at day 7 in both treated (p<0.0001) and contralateral tumors (p≤0.0004), indicating activation of cytotoxic immunity. Serum cytokine analysis revealed transient early increases in TNFalpha and IL-17, with persistent IFN-gamma elevation at day 7, suggesting sustained systemic immune activation. Mechanistically, preservation of tumor vasculature and antigen integrity following non-thermal ablation may facilitate antigen presentation and T-cell priming. This study provides the first evidence that PFA is effective against PDAC and capable of converting an immune-cold tumor into an immune-active phenotype. PFA induced extensive local necrosis, enhanced cytotoxic T-cell infiltration, and triggered a systemic abscopal response. These findings position PFA as a promising dual-action platform-combining direct cytotoxicity with durable immune stimulation-and support its development in combination with immunotherapy to overcome the resistance of PDAC to immune checkpoint blockade.