Cao Yuan, Zhao Zixuan, Fang Junyue, Lu Yanan, Huang Zhuoshan, Wu Guo, Gao Qiyuan, Li Rong, Xu Lei, Xu Xiaoding
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.
Guangzhou Key Laboratory of Medical Nanomaterials, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.
Adv Healthc Mater. 2025 Jun;14(16):e2500646. doi: 10.1002/adhm.202500646. Epub 2025 May 20.
Immune checkpoint blockade (ICB) therapy has become the first-line treatment for cancer patients. However, the low response rate remains a clinical pain-point. Anti-hyperglycemic drug metformin has shown remarkable anticancer effect with the unique characteristic of modulating tumor immune microenvironment (TIME). Therefore, combining ICB with metformin could be a promising strategy for enhanced cancer immunotherapy, which however remains challenged due to the low bioavailability and severe adverse effects of metformin. This work herein designs an amphiphilic reduction-responsive metformin prodrug, which could complex small interfering RNA (siRNA) and then co-assemble with an endosomal pH-responsive PEGylated polymer to form a dual-responsive immunomodulatory RNAi nanoplatform. Using the orthotopic and metastatic breast cancer (BCa) tumor models, this work demonstrates that this RNAi nanoplatform could silence PD-L1 expression on BCa cells and suppress their proliferation via activating AMP-activated protein kinase (AMPK). Moreover, this AMPK activation could suppress the secretion of tumor-derived transforming growth factor β (TGF-β) and interleukin 6 (IL-6), which could enhance the maturation of dendritic cells (DCs) and activation of CD8 T cells and impair the tumor infiltration of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), ultimately achieving the goal of enhanced cancer immunotherapy and significant inhibition of BCa tumor growth.
免疫检查点阻断（ICB）疗法已成为癌症患者的一线治疗方法。然而，低反应率仍然是一个临床痛点。抗高血糖药物二甲双胍已显示出显著的抗癌作用，具有调节肿瘤免疫微环境（TIME）的独特特性。因此，将ICB与二甲双胍联合使用可能是增强癌症免疫治疗的一种有前景的策略，然而，由于二甲双胍的低生物利用度和严重的副作用，这一策略仍然面临挑战。本文设计了一种两亲性还原响应型二甲双胍前药，它可以与小干扰RNA（siRNA）复合，然后与一种内体pH响应型聚乙二醇化聚合物共同组装，形成一种双响应免疫调节RNAi纳米平台。利用原位和转移性乳腺癌（BCa）肿瘤模型，本文证明了这种RNAi纳米平台可以沉默BCa细胞上的PD-L1表达，并通过激活AMP激活的蛋白激酶（AMPK）抑制其增殖。此外，这种AMPK激活可以抑制肿瘤来源的转化生长因子β（TGF-β）和白细胞介素6（IL-6）的分泌，这可以增强树突状细胞（DCs）的成熟和CD8 T细胞的激活，并损害调节性T细胞（Tregs）、髓源性抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs）的肿瘤浸润，最终实现增强癌症免疫治疗和显著抑制BCa肿瘤生长的目标。
