Pyroptosis, an immunogenic programmed cell death, could efficiently activate tumor immunogenicity and reprogram immunosuppressive microenvironment for boosting cancer immunotherapy. However, the overexpression of SLC7A11 promotes glutathione biosynthesis for maintaining redox balance and countering pyroptosis. Herein, we develop intermetallics modified with glucose oxidase (GOx) and soybean phospholipid (SP) as pyroptosis promoters (Pd₂Sn@GOx-SP), that not only induce pyroptosis by cascade biocatalysis for remodeling tumor microenvironment and facilitating tumor cell immunogenicity, but also trigger disulfidptosis mediated by cystine accumulation to further promote tumor pyroptosis in female mice. Experiments and density functional theory calculations show that Pd₂Sn nanorods with an intermediate size exhibit stronger photothermal and enzyme catalytic activity compared with the other three morphologies investigated. The peroxidase-mimic and oxidase-mimic activities of Pd₂Sn cause potent reactive oxygen species (ROS) storms for triggering pyroptosis, which could be self-reinforced by photothermal effect, hydrogen peroxide supply accompanied by glycometabolism, and oxygen production from catalase-mimic activity of Pd₂Sn. Moreover, the increase of NADP⁺/NADPH ratio induced by glucose starvation could pose excessive cystine accumulation and inhibit glutathione synthesis, which could cause disulfidptosis and further augment ROS-mediated pyroptosis, respectively. This two-pronged treatment strategy could represent an alternative therapeutic approach to expand anti-tumor immunotherapy.

焦亡是一种免疫原性程序性细胞死亡，可以有效地激活肿瘤免疫原性并重新编程免疫抑制微环境以促进癌症免疫治疗。然而，SLC7A11 的过表达会促进谷胱甘肽的生物合成，以维持氧化还原平衡和对抗焦亡。在此，我们开发了以葡萄糖氧化酶 （GOx） 和大豆磷脂 （SP） 作为焦亡促进剂 （Pd₂Sn@GOx-SP） 修饰的金属间化合物，其不仅通过级联生物催化诱导焦亡，重塑肿瘤微环境并促进肿瘤细胞免疫原性，还触发胱氨酸积累介导的二硫下垂，进一步促进雌性小鼠的肿瘤焦亡。实验和密度泛函理论计算表明，与所研究的其他三种形态相比，具有中等尺寸的 Pd₂Sn 纳米棒表现出更强的光热和酶催化活性。Pd₂Sn 的过氧化物酶模拟物和氧化酶模拟物活性会引起有效的活性氧 （ROS） 风暴以触发焦亡，这可能通过光热效应、伴随糖代谢的过氧化氢供应以及 Pd₂Sn 的过氧化氢酶模拟活性产生氧气来自我增强。此外，葡萄糖饥饿诱导的 NADP⁺/NADPH 比值增加可导致胱氨酸过度积累并抑制谷胱甘肽合成，分别导致二硫下垂并进一步增强 ROS 介导的焦亡。这种双管齐下的治疗策略可能代表一种扩展抗肿瘤免疫疗法的替代治疗方法。