肿瘤细胞治疗研究
英文原题：A Probiotic Approach Targeting Hypersialylation Revives CD8+ T-cell Immunity and Boosts Photodynamic Therapy Efficacy in Solid Tumors.
未标注：肿瘤聚糖上过量的末端唾液酸与抑制性Siglec受体结合，并掩盖肽和聚糖表位，包括主要组织相容性复合体I类（MHC-I），从而降低抗原可见性并削弱细胞毒性T细胞监视。
未标注：肿瘤聚糖上过量的末端唾液酸会结合抑制性 Siglec 受体，并掩盖肽表位和聚糖表位，包括主要组织相容性复合体 I 类（MHC-I），从而降低抗原可见性并抑制细胞毒性 T 细胞监视。在本研究中，我们证明一种紧凑、无凝集素的鼠伤寒沙门菌唾液酸酶（Sia）可高效去除黑色素瘤和结直肠癌细胞表面的唾液酸，消除 Siglec-E 结合，并使 MHC-I 免于溶酶体降解。在功能上，Sia 处理增强了树突状细胞吞噬作用和肿瘤抗原呈递，扩增了 IFNγ+/granzyme B+ CD8+ T 细胞，并以 CD8+ T 细胞依赖性方式减缓肿瘤生长，且无全身毒性。将益生菌大肠杆菌 Nissle 1917 工程化以共表达光敏剂 KillerRed（KR）和 Sia（ProKR/Sia），可实现局部靶向。瘤内递送后，ProKR/Sia 选择性定植于缺氧肿瘤核心，同时不损伤健康组织；未检测到脱靶去唾液酸化或器官定植。短暂白光照射裂解细菌，同步释放 Sia 以重塑肿瘤聚糖，并激活 KR 产生活性氧，从而驱动免疫原性细胞死亡。在同系小鼠肿瘤模型中，ProKR/Sia 光动力疗法（PDT）优于任一单药治疗，并诱导强健的细胞免疫，表现为细胞毒性 CD8+ 和 CD4+ T 细胞扩增以及多种先天免疫反应，包括NK 细胞活化和 M1 样巨噬细胞极化。此外，ProKR/Sia PDT 建立了抗原特异性记忆，可排斥再次攻击。这些数据定义了一种空间受限、抗原不可知的策略，可恢复MHC-I可见性并在免疫“冷”肿瘤中激活抗肿瘤免疫，从而产生持久应答。与免疫治疗、深部组织照明和可编程生物安全开关的合理联合可能进一步克服肿瘤抗原异质性并拓宽临床适用性。意义：益生菌唾液酸酶-KillerRed光动力疗法通过恢复抗原可见性并点燃持久抗肿瘤T细胞应答，克服高唾液酸化介导的免疫抑制，为治疗实体瘤提供了一种抗原不可知平台。
UNLABELLED: Excess terminal sialic acids on tumor glycans engage inhibitory Siglec receptors and mask peptide and glycan epitopes, including major histocompatibility complex class I (MHC-I), thereby reducing antigen visibility and dampening cytotoxic T-cell surveillance. In this study, we showed that a compact, lectin-free Salmonella typhimurium sialidase (Sia) efficiently desialylated melanoma and colorectal carcinoma cells, abolished Siglec-E binding, and spared MHC-I from lysosomal degradation. Functionally, Sia treatment enhanced dendritic cell phagocytosis and tumor antigen presentation, expanded IFNγ+/granzyme B+ CD8+ T cells, and slowed tumor growth in a CD8+ T cell-dependent manner without systemic toxicity. Engineering the probiotic Escherichia coli Nissle 1917 to coexpress the photosensitizer KillerRed (KR) and Sia (ProKR/Sia) enabled localized targeting. Following intratumoral delivery, ProKR/Sia selectively colonized hypoxic tumor cores while sparing healthy tissues; no off-target desialylation or organ colonization was detected. Brief white-light irradiation lysed the bacteria, synchronously releasing Sia to remodel tumor glycans and activating KR to generate reactive oxygen species that drive immunogenic cell death. In syngeneic murine tumor models, ProKR/Sia photodynamic therapy (PDT) outperformed either monotherapy and induced robust cellular immunity with expansion of cytotoxic CD8+ and CD4+ T cells and multiple innate responses, including natural killer cell activation and M1-like macrophage polarization. Furthermore, ProKR/Sia PDT established antigen-specific memory that rejected rechallenge. These data define a spatially confined, antigen-agnostic strategy that restores MHC-I visibility and activates antitumor immunity in immunologically "cold" tumors, leading to a durable response. Rational combinations with immunotherapy, deep-tissue illumination, and programmable biosafety switches may further overcome tumor antigen heterogeneity and broaden clinical applicability. SIGNIFICANCE: Probiotic sialidase-KillerRed photodynamic therapy overcomes hypersialylation-mediated immunosuppression by restoring antigen visibility and igniting durable antitumor T-cell responses, offering an antigen agnostic platform for treating solid tumors.
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