撰文丨王聪 编辑丨王多鱼 排版丨水成文 免疫原性细胞死亡 （ Immunogenic cell death， ICD） 是一种很有前景的方法，可用于激发抗肿瘤免疫反应，从而治疗癌症患者。然而，免疫原性细胞死亡的 立体定向诱导以及肿瘤特异性免疫反应的时空同步激活，构成了两大关键挑战。 2025 年 11 月 19 日，中国药科大学 尹骏 、 高向东 、 童玥 等人在 Science 子刊 Science Translational Medicine 上发表了题为： A modular metalloprotein in situ vaccine for cancer immunotherapy in mouse models of breast cancer 的研究论文。 在这项最新研究中，研究团队报道了一种 蛋白酶激活的 聚多肽 （PSTAG） 修饰的 原位肿瘤疫苗 （PPTV） 的模块化金属蛋白平台的基本原理和系统性开发。 研究团队利用铁蛋白作为疫苗框架，其外表面融合了最佳线粒体破坏肽，内腔装载锰离子 （Mn²⁺） 。此外，研究团队开发了蛋白酶激活的 PSTAG 修饰的前药策 略，以规避铁蛋白相关的主要问题 ...

Core Viewpoint - Immunotherapy, particularly immune checkpoint blockade (ICB), has transformed cancer treatment but remains ineffective in "cold tumors" due to immune suppression in the tumor microenvironment (TME) [2][5][6] Group 1: Research Findings - A new biomimetic Ru/TiO₂ nanobiocatalyst system inspired by natural enzyme reaction systems (ERS) has been developed, capable of rapid, pH-dependent generation of reactive oxygen species (ROS) and oxygen (O₂), effectively converting cold tumors into hot tumors [3][6][7] - The Ru/TiO₂ system enhances anti-tumor immunity and suppresses tumor metastasis when used in conjunction with ICB therapy [3][7] - This research establishes a precedent for adaptive nanobiocatalysts in the TME and paves the way for the development of next-generation immunotherapies targeting drug-resistant cancers [3][6] Group 2: Mechanism of Action - The study demonstrates that Ru/TiO₂ can mediate immunogenic cell death (ICD) in melanoma cells through endoplasmic reticulum stress, while also inhibiting hypoxia-induced immune suppression [7] - The design of Ru/TiO₂ aims to reverse immune suppression and enhance immunogenicity, transforming "immune cold" tumors into "immune hot" tumors [7] Group 3: Clinical Implications - The findings suggest that the rational design of robust and efficient biocatalytic materials could extend beyond cancer treatment, opening new avenues for immune modulation in other diseases [3][6]

Core Viewpoint - The article discusses the development of a biomimetic nanoimmunotherapy that induces PANoptosis to reshape the desmoplastic tumor microenvironment, enhancing anti-tumor immunity and reducing recurrence risk while inhibiting metastasis [3][8]. Group 1: Challenges in Cancer Immunotherapy - Dendritic cell (DC)-based vaccines face significant challenges in solid tumors, including the lack of tumor-specific antigens and the immunosuppressive stroma present in these tumors [5][6]. - Traditional DC vaccines have limited clinical success due to issues such as antigen degradation and immune tolerance, prompting the exploration of hybrid cells formed by fusing DCs with tumor cells [5][6]. Group 2: Innovative Approaches - The study introduces a therapeutic nano-vaccine, UCNP@MOF@MI@FM (UMMF), which combines dendritic cell and tumor hybrid cell membranes, co-loaded with MTH1 inhibitors and tetrahydrobiopterin (BH4) [6][7]. - This platform aims to induce immunogenic cell death (ICD) through PANoptosis, enhancing the activation of cytotoxic T lymphocytes (CTLs) and reprogramming the tumor microenvironment [6][7]. Group 3: Key Findings - The biomimetic nano-vaccine triggers reactive oxygen species (ROS)-induced immunogenic PANoptosis in a spatiotemporal manner [8]. - Near-infrared (NIR) light programming therapy is effective in reshaping the immunosuppressive tumor microenvironment [8]. - The synergistic effect of BH4 with the UMMF nano-vaccine can combat immune therapy resistance [8].