理由：新辅助化疗（NAC）已被认为是晚期恶性肿瘤不可或缺的策略。然而，由于其疗效的持续性有限且无法预防术后肿瘤复发和转移，NAC接受者总体患者生存率的提高遇到了挑战。方法：我们设计了一种分层解锁的 nanoSTING 刺激脂质体（AUG）作为新辅助化学免疫治疗剂，通过同时激活先天性和适应性抗肿瘤免疫反应来在术前减灭肿瘤并预防术后肿瘤复发和转移。在弱酸性肿瘤微环境中，AUG内的腙键最初断裂，导致释放含有叔胺的环状七元环，其用于激活干扰素基因刺激剂（STING）途径。此后，AUG 在溶酶体内经历降解，促进阿霉素的释放，最终诱导免疫原性细胞死亡，同时双链 DNA 渗漏到细胞质中。结果：分级酸度解锁模式能够级联 STING 激活，在皮下异种移植模型中实现超过 90% 的肿瘤生长抑制，并与免疫检查点抑制剂联合使用，防止 75% 的小鼠术后转移或复发。结论：我们的策略强调了 AUG 作为术前肿瘤减灭的新辅助范例以及作为术后肿瘤复发和转移的预防措施的效力。© 作者。

Rationale: Neoadjuvant chemotherapy (NAC) has been recognized as an indispensable strategy for advanced malignancies. Nevertheless, the enhancement of overall patient survival in NAC recipients has encountered challenges due to the limited sustainability of its efficacy and the inability to prevent postoperative tumor recurrence and metastasis. Methods: We devise a hierarchically unlocking nanoSTING stimulant liposome (AUG) as a neoadjuvant chemoimmunotherapy agent in the debulking of tumors prior to surgery and prevention of postoperative tumor recurrence and metastasis by simultaneously activating innate and adaptive antitumor immune responses. In the weakly acidic tumor microenvironment, the hydrazone bond within AUG is initially cleaved, leading to the release of a cyclic seven-membered ring containing tertiary amine that serve to activate the stimulator of interferon genes (STING) pathway. Following this, AUG undergoes degradation within lysosomes, facilitating the release of doxorubicin and ultimately inducing immunogenic cell death along with leakage of double-stranded DNA into the cytoplasm. Results: The hierarchically acidity-unlocking pattern enables cascaded STING activation, achieving over 90% tumor growth inhibition in subcutaneous xenograft model and preventing 75% of mice from postsurgical metastasis or recurrence when combined with immune checkpoint inhibitors. Conclusion: Our strategy highlights the potency of AUG as a neoadjuvant paradigm for presurgical tumor debulking and as a preventive measure against postoperative tumor recurrence and metastasis.© The author(s).