NCLX Inhibition plus Ca ²⁺ Delivery Potentiates Electroporation and Antitumor Immunity in Pancreatic Ductal Adenocarcinoma

ABSTRACT

Irreversible electroporation (IRE) is increasingly used for locally advanced pancreatic ductal adenocarcinoma (PDAC), yet electric‐field heterogeneity leaves a low‐field rim where residual cells survive, and recurrence is frequent, compounded by a profoundly immunosuppressive tumor microenvironment. Here, an electroporation‐synchronized adjuvant strategy is developed that integrates intratumoral Ca ²⁺ delivery with nanoparticle‐mediated inhibition of mitochondrial NCLX using CGP37157 (mPEG–PCL@CGP37157). This regimen markedly enhances cytotoxicity in PDAC cell lines and patient‐derived organoids and significantly improves local control and survival in syngeneic subcutaneous and orthotopic PDAC models, without overt systemic toxicity. Reduced therapeutic efficacy in T cell–deficient hosts demonstrates the importance of adaptive immunity. Mechanistically, EP‐resistant PDAC cells upregulate NCLX to buffer mitochondrial Ca ²⁺ stress. Concurrent Ca ²⁺ delivery and pharmacological NCLX inhibition induce sustained mitochondrial Ca ²⁺ overload, triggering immunogenic GSDMD‐dependent pyroptosis. This is accompanied by enhanced dendritic cell activation and CD8 ⁺ T‐cell responses, as well as suppression of a tumor–myeloid SPP1–CD44 axis, promoting pro‐inflammatory macrophage polarization. Collectively, targeting NCLX potentiates the immunogenic effects of IRE and provides a translatable strategy for eliminating residual disease in PDAC.