胰腺导管腺癌（PDAC）已迅速成为美国癌症相关死亡的第三大原因。这部分是因为其纤维化肿瘤微环境（TME）导致血管化和免疫浸润不良以及随后的化疗和免疫治疗失败。在这里，我们研究了一种免疫治疗方法，通过脂质纳米颗粒 (NP) 共封装传递干扰素基因刺激剂 (STING) 和 Toll 样受体 4 (TLR4) 先天免疫激动剂与诱导衰老的 RAS 靶向疗法相结合，该疗法可以重塑通过衰老相关的分泌表型来抑制免疫抑制 PDAC TME。用这些方案治疗移植和本地 PDAC 小鼠模型导致 PDAC TME 中多种细胞类型对 NP 的摄取增强，诱导 I 型干扰素和其他促炎信号通路，增加肿瘤细胞和抗原呈递细胞的抗原呈递，并随后激活先天性和适应性免疫反应。这种双管齐下的方法在依赖于肿瘤和宿主 STING 激活的临床前 PDAC 模型中产生了有效的 T 细胞驱动和 I 型干扰素介导的肿瘤消退和长期存活。 STING 和 TLR4 介导的 I 型干扰素信号传导还与人类 PDAC 样本中自然杀伤细胞和 CD8 T 细胞免疫增强有关。因此，将局部免疫激动剂递送与全身性肿瘤靶向治疗相结合，可以协调 I 型干扰素驱动的先天性和适应性免疫反应，并对 PDAC 具有持久的抗肿瘤功效。

Pancreatic ductal adenocarcinoma (PDAC) has quickly risen to become the third leading cause of cancer-related death in the United States. This is in part because of its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here, we investigated an immunotherapy approach combining delivery of stimulator of interferon genes (STING) and Toll-like receptor 4 (TLR4) innate immune agonists by lipid-based nanoparticle (NP) coencapsulation with senescence-inducing RAS-targeted therapies, which can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other proinflammatory signaling pathways, increased antigen presentation by tumor cells and antigen-presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and type I interferon-mediated tumor regression and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated type I interferon signaling was also associated with enhanced natural killer and CD8+ T cell immunity in human PDAC samples. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can orchestrate a coordinated type I interferon-driven innate and adaptive immune response with durable antitumor efficacy against PDAC.