免疫原性细胞死亡（ICD）具有原位肿瘤疫苗接种的潜力，同时可以根除肿瘤并刺激适应性免疫。然而，由于针对 ICD 生物标志物的负反馈、抗肿瘤免疫细胞的浸润有限以及免疫抑制肿瘤微环境 (TME)，大多数 ICD 诱导剂引起的免疫反应不足。最近的研究结果强调了干扰素基因 (STING) 激活刺激剂的关键作用，特别是在刺激抗原呈递细胞 (APC) 和 TME 重编程、解决 ICD 局限性方面。在此，我们介绍了“肿瘤吞噬作用驱动的 STING 激活”，这涉及在识别 ICD 诱导的癌细胞期间 APC 中 STING 的激活。我们开发了一种封装阿霉素 (DOX) 和 diABZI STING 激动剂 3 (dSA3) 的基于多肽的纳米载体，以在体外和体内促进这一假设。全身给药后，纳米颗粒主要积聚在肿瘤组织中，并通过激活 MC38 和 TC1 肿瘤模型中肿瘤吞噬作用驱动的 STING 激活来显着增强抗癌功​​效。 APC 的免疫激活发生在 12 小时内，随后导致 T 细胞在 7 天内激活，这在 TME 和脾脏中均观察到。此外，用环状RGD（cRGD）部分对纳米颗粒进行表面修饰，主动靶向整合素αvβ3，增强肿瘤的积累和根除，从而验证全身免疫记忆的建立。总的来说，这项研究提出了肿瘤吞噬作用驱动的 STING 激活的概念及其在产生短期和长期免疫反应方面的有效性。版权所有 © 2024。由 Elsevier B.V. 出版。

Immunogenic cell death (ICD) holds the potential for in situ tumor vaccination while concurrently eradicating tumors and stimulating adaptive immunity. Most ICD inducers, however, elicit insufficient immune responses due to negative feedback against ICD biomarkers, limited infiltration of antitumoral immune cells, and the immunosuppressive tumor microenvironment (TME). Recent findings highlight the pivotal roles of stimulators of interferon gene (STING) activation, particularly in stimulating antigen-presenting cells (APCs) and TME reprogramming, addressing ICD limitations. Herein, we introduced 'tumor phagocytosis-driven STING activation', which involves the activation of STING in APCs during the recognition of ICD-induced cancer cells. We developed a polypeptide-based nanocarrier encapsulating both doxorubicin (DOX) and diABZI STING agonist 3 (dSA3) to facilitate this hypothesis in vitro and in vivo. After systemic administration, nanoparticles predominantly accumulated in tumor tissue and significantly enhanced anticancer efficacy by activating tumor phagocytosis-driven STING activation in MC38 and TC1 tumor models. Immunological activation of APCs occurred within 12 h, subsequently leading to the activation of T cells within 7 days, observed in both the TME and spleen. Furthermore, surface modification of nanoparticles with cyclic RGD (cRGD) moieties, which actively target integrin αvβ3, enhances tumor accumulation and eradication, thereby verifying the establishment of systemic immune memory. Collectively, this study proposes the concept of tumor phagocytosis-driven STING activation and its effectiveness in generating short-term and long-term immune responses.Copyright © 2024. Published by Elsevier B.V.