摘要
A pH-responsive nanoplatform was developed to enhance gastric cancer chemo-immunotherapy. • Tumor acidity-triggered charge reversal improved intracellular delivery of oxaliplatin and BAPTA-AM. • Calcium chelation blocked pyroptosis reversibility and amplified immunogenic cell death. • The nanoplatform weakened tumor stemness and reshaped the immune microenvironment. The clinical response rate of combined chemotherapy and immunotherapy in gastric cancer remains unsatisfactory, largely due to insufficient release of tumor antigens and immunogenic cell death signals under treatment-tolerant conditions, as well as immune evasion driven by cancer stem cells (CSCs). To address this, this study constructed a membrane-affinity intelligent nanodelivery system (pHP + -O/B) that responds to the acidic tumor microenvironment, for the co-delivery of oxaliplatin and the calcium ion chelator BAPTA-AM. Under acidic tumor conditions, pHP + -O/B undergoes PEG detachment and exposes a positively charged core, enhancing its interaction with gastric cancer cell membranes and improving intracellular drug delivery. Mechanistically, oxaliplatin induces GSDME-mediated pyroptosis, while BAPTA-AM synergistically amplifies this effect by blocking calcium dependent membrane repair processes, thereby significantly promoting the release of immunogenic molecules such as HSP70 and HMGB1 and remodeling the tumor immune microenvironment. Further investigations reveal that this strategy effectively suppresses Wnt/β-catenin associated stemness signaling, reduces the CSCs population, enhances DC maturation and promotes T-cell activation. Patient-derived xenograft (PDX) models further confirmed the antitumor efficacy of pHP + -O/B and its ability to enhance pyroptosis and suppress tumor stemness. In summary, we present a nano-delivery strategy that synergistically amplifies pyroptosis and suppresses tumor stemness, thereby enhancing chemo-immunotherapy efficacy in gastric cancer.
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