Abstract：
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 micro-environment (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.
摘要：
免疫原性细胞死亡（ICD）具有原位肿瘤疫苗接种的潜力，同时根除肿瘤并刺激适应性免疫。大多数ICD诱导剂，然而,由于对ICD生物标志物的负反馈，引起免疫反应不足，抗肿瘤免疫细胞的有限浸润，和免疫抑制肿瘤微环境（TME）。最近的发现强调了干扰素基因（STING）激活刺激物的关键作用，特别是在刺激抗原呈递细胞（APC）和TME重编程中，解决ICD的局限性。在这里，我们引入了“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。我们开发了一种基于多肽的纳米载体，同时封装了阿霉素（DOX）和diABZISTING激动剂3（dSA3），以在体外和体内促进这一假设。全身给药后，纳米颗粒主要积累在肿瘤组织中，并通过激活MC38和TC1肿瘤模型中的肿瘤吞噬作用驱动的STING激活而显着增强抗癌功效。APC的免疫激活发生在12小时内，随后导致7天内T细胞的激活，在TME和脾脏中观察到。此外，具有环状RGD（cRGD）部分的纳米颗粒的表面改性，积极靶向整合素αvβ3，增强肿瘤的积累和根除，从而验证了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中的有效性。
