“Alkaline‐Hammer Strategy” Breaks Acidic and Stromal Barriers to Induce Alkaliptosis and Enhance Immunotherapy in Pancreatic Cancer

ABSTRACT Immunotherapy for pancreatic cancer remains a formidable challenge due to the highly immunosuppressive tumor microenvironment (TME), characterized by dense stromal barriers and acidic niches that collectively restrict drug delivery and antitumor immunity. Here, we propose an “Alkaline‐Hammer” strategy that combines pH modulation with alkaliptosis induction to overcome these obstacles. We engineered alkalizing sodium bicarbonate nanoparticles (JTC801‐NaHCO 3 @TPGS NPs) using a thin‐film hydration method. Upon delivery, these nanoparticles neutralize the acidic TME through sustained NaHCO 3 release, while JTC801, a selective opioid receptor‐like 1 (ORL1) antagonist, activates the NF‐κB pathway to downregulate carbonic anhydrase IX (CA9). This dual action synergistically enhances intracellular alkalinization and induces alkaliptosis. Furthermore, we developed a laparoscopic intratumoral injection system to achieve precise delivery of JTC801‐NaHCO 3 @TPGS NPs in orthotopic pancreatic tumor models. This strategy increased CD8 + T cells infiltration, reduced immunosuppressive populations (Tregs, MDSCs, and M2 macrophages), and elicited immunological memory, thereby converting immunologically “cold” tumors into “hot” ones without evident systemic toxicity. These findings underscore the potential of localized alkaliptosis induction as a promising immunotherapeutic approach for pancreatic cancer.