Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, P. R. China.
Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
J Am Chem Soc. 2023 Aug 30;145(34):18789-18799. doi: 10.1021/jacs.3c03031. Epub 2023 Aug 3.
Despite the tremendous breakthrough of immunotherapy, the low response rate and resistance of immune checkpoint inhibitors (ICIs) toward solid tumors occur frequently. A highly hypoxic tumor microenvironment (TME) provides tumor cells with high concentrations of HIF-1α and polyamines to evade immune cell destruction. Reprogramming of an immunogenic TME has exhibited a brilliant future to boost immunotherapeutic performances. Herein, a supramolecular nanomedicine () is developed on the basis of host-guest molecular recognition and metal coordination, showing the capability to remodel the immunosuppressive TME. Tamoxifen () and Fe are encapsulated into to achieve the combination of chemotherapy and chemodynamic therapy (CDT). directly downregulates HIF-1α, and a pillar[5]arene-based macrocyclic host successfully eliminates polyamines in tumors. Enhanced immunogenic cell death is achieved by and Fe, and the therapeutic efficacy is further synergized by immune checkpoint blockade (ICB) therapy. This supramolecular reprogramming modality encourages cytotoxic T lymphocyte infiltration, achieving pre-eminent immune response and long-term tumor suppression.
尽管免疫疗法取得了巨大突破，但免疫检查点抑制剂（ICIs）对实体瘤的低反应率和耐药性经常发生。高度缺氧的肿瘤微环境（TME）为肿瘤细胞提供高浓度的 HIF-1α 和聚胺，以逃避免疫细胞的破坏。重塑免疫原性 TME 展现了增强免疫治疗效果的美好前景。在此，基于主客体分子识别和金属配位，开发了一种超分子纳米医学（），具有重塑免疫抑制 TME 的能力。他莫昔芬（）和 Fe 被包封到中，以实现化疗和化学动力学治疗（CDT）的联合。直接下调 HIF-1α，基于柱芳烃的大环主体成功消除了肿瘤中的聚胺。通过和 Fe 实现增强的免疫原性细胞死亡，免疫检查点阻断（ICB）治疗进一步协同增效。这种超分子重编程方式促进了细胞毒性 T 淋巴细胞的浸润，实现了卓越的免疫反应和长期的肿瘤抑制。
