胰腺导管腺癌（PDAC）由于其高致死率和对免疫治疗的抵抗力而对肿瘤学提出了挑战。最近，关于干扰素基因刺激物（STING）途径的新兴研究为免疫治疗提供了新的机会。尽管 STING 表达保留在 PDAC 细胞中，但 PDAC 细胞对 STING 激动剂的反应仍然无效。信号转导子和转录激活子 3 (STAT3) 是 STING 的下游通路，在胰腺癌中显着过度表达，与肿瘤存活和免疫逃逸相关。我们观察到，抑制 STING 激活后的 STAT3 信号传导可通过信号转导器和转录激活剂 1 (STAT1) 介导的细胞凋亡有效抑制肿瘤生长，但会导致免疫相关不良事件 (irAE) 的潜在风险。为了解决这个问题，我们设计了一种肿瘤穿透脂质体，用于同时递送 STING 激动剂和 STAT3 抑制剂。这些纳米颗粒调节STING/STAT3信号轴并有效抑制肿瘤的增殖和存活。同时，我们发现治疗后 NK 细胞和 CD8 T 细胞的活化显着增加，从而产生强大的先天免疫和适应性免疫反应。我们强调调节 STING/STAT3 轴作为改善 PDAC 患者临床结果的有希望的治疗方法的潜力。

Pancreatic ductal adenocarcinoma (PDAC) poses a challenge in oncology due to its high lethality and resistance to immunotherapy. Recently, emerging research on the stimulator of interferon gene (STING) pathway offers novel opportunities for immunotherapy. Although STING expression is retained in PDAC cells, the response of PDAC cells to STING agonists remains ineffective. Signal transducer and activator of transcription 3 (STAT3), a downstream pathway of STING, is notably overexpressed in pancreatic cancer and related to tumor survival and immune escape. We observed that inhibiting STAT3 signaling post-STING activation effectively suppressed tumor growth through signal transducer and activator of transcription 1 (STAT1)-mediated apoptosis but led to a potential risk of immune-related adverse events (irAEs). To address this issue, we designed a tumor-penetrating liposome for the codelivery of STING agonist and STAT3 inhibitor. These nanoparticles regulated the STING/STAT3 signaling axis and effectively inhibited the proliferation and survival of tumor. Simultaneously, we found a significant increase in the activation of NK cells and CD8+ T cells after treatment, leading to robust innate immunity and adaptive immune response. We highlight the potential of regulating the STING/STAT3 axis as a promising treatment for improving clinical outcomes in PDAC patients.