顺铂是肺腺癌（LUAD）的一线化疗药物。然而，严重的副作用和获得性药物耐药限制了其治疗效果。靶向HER2已被证明是一种可行的LUAD治疗策略。此外，inetetamab是一种创新的抗HER2单克隆抗体，其比曲妥珠单抗具有更强的抗体依赖性细胞介导的细胞毒作用（ADCC）诱导作用，该策略已被证明是在临床中与多种化疗药物联合应用的有效和合理策略。因此，本研究旨在探讨顺铂（DDP）和inetetamab在LUAD细胞中的协同效应，并研究其详细的潜在机制。在体外和体内实验中，我们发现inetetamab和顺铂的联合应用可以诱导LUAD细胞发生协同作用，包括诱导焦亡。机制研究揭示，inetetamab与顺铂的联合应用抑制了HER2/AKT/Nrf2信号通路，增加了ROS水平，进而触发NLRP3/caspase-1/GSDMB介导的焦亡，从而协同增强了LUAD细胞的抗肿瘤效果。此外，顺铂通过诱导GSDMB介导的焦亡增强了inetetamab对PBMC的杀伤能力，这可以通过IFN-γ分泌的增加来解释。我们的研究揭示了抗HER2单克隆抗体inetetamab可能是LUAD治疗的理想选择，并为LUAD的治疗干预提供了新的途径。©作者。

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms. Here, in vitro and in vivo, we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ. Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.© The author(s).