光热敏感金纳米笼增强免疫“冷”肿瘤中免疫检查点阻断的抗肿瘤效率。

INTRODUCTION: Immune checkpoint blockade (ICB) has revolutionized the therapy landscape of malignancy melanoma. However, the clinical benefits from this regimen remain limited, especially in tumors lacking infiltrated T cells (known as "cold" tumors). Nanoparticle-mediated photothermal therapy (PTT) has demonstrated improved outcomes in the ablation of solid tumors by inducing immunogenic cell death (ICD) and reshaping the tumor immune microenvironment. Therefore, the combination of PTT and ICB is a promising regimen for patients with "cold" tumors. METHODS: A second near-infrared (NIR-II) light-activated gold nanocomposite AuNC@SiO@HA with AuNC as a kernel, silica as shell, and hyaluronic acid (HA) polymer as a targeting molecule, was synthesized for PTT. The fabricated AuNC@SiO@HA nanocomposites underwent various studies to characterize their physicochemical properties, light absorption spectra, photothermal conversion ability, cellular uptake ability, and bioactivities. The synergistic effect of AuNC@SiO@HA-mediated PTT and anti-PD-1 immunotherapy was evaluated using a mouse model of immune "cold" melanoma. The tumor-infiltrating T cells were assessed by immunofluorescence staining and flow cytometry. Furthermore, the mechanism of AuNC@SiO@HA-induced T-cell infiltration was investigated through immunochemistry staining of the ICD-related markers, including HSP70, CRT, and HMGB1. Finally, the safety of AuNC@SiO@HA nanocomposites was evaluated . RESULTS: The AuNC@SiO@HA nanocomposite with absorption covering 1064 nm was successfully synthesized. The nano-system can be effectively delivered into tumor cells, transform the optical energy into thermal energy upon laser irradiation, and induce tumor cell apoptosis . In an mouse melanoma model, AuNC@SiO@HA nanocomposites significantly induced ICD and T-cell infiltration. The combination of AuNC@SiO@HA and anti-PD-1 antibody synergistically inhibited tumor growth stimulating robust T lymphocyte immune responses. DISCUSSION: The combination of AuNC@SiO@HA-mediated PTT and anti-PD-1 immunotherapy proposed a neoteric strategy for oncotherapy, which efficiently convert the immune "cold" tumors into "hot" ones.

简介：免疫检查点阻断（ICB）彻底改变了恶性黑色素瘤的治疗格局。然而，这种疗法的临床获益仍然有限，特别是在缺乏浸润 T 细胞的肿瘤中（称为“冷”肿瘤）。纳米颗粒介导的光热疗法（PTT）通过诱导免疫原性细胞死亡（ICD）和重塑肿瘤免疫微环境，已证明在消融实体瘤方面具有更好的效果。因此，PTT 与 ICB 的联合治疗方案有望应用于“冷”肿瘤患者。

方法：我们合成了一种新型的近红外二区（NIR-II）光激活金纳米复合物 AuNC@SiO@HA，其内核为 AuNC，外壳为二氧化硅（SiO），靶向分子为透明质酸（HA）聚合物，用于 PTT。制备的 AuNC@SiO@HA 纳米复合材料经过多种研究，以表征其物理化学性质、光吸收光谱、光热转换能力、细胞摄取能力和生物活性。通过免疫“冷”黑色素瘤小鼠模型评估了 AuNC@SiO@HA 介导的 PTT 和抗 PD-1 免疫治疗的协同效应。通过免疫荧光染色和流式细胞术评估肿瘤浸润 T 细胞。此外，通过免疫化学染色检测 ICD 相关标志物，包括 HSP70、CRT 和 HMGB1，研究了 AuNC@SiO@HA 诱导 T 细胞浸润的机制。最后，评估了 AuNC@SiO@HA 纳米复合材料的安全性。

结果：成功合成了吸收覆盖 1064nm 的 AuNC@SiO@HA 纳米复合材料。该纳米系统可以有效地递送到肿瘤细胞中，在激光照射下将光学能量转化为热能，并诱导肿瘤细胞凋亡。在小鼠黑色素瘤模型中，AuNC@SiO@HA 纳米复合材料显著诱导 ICD 和 T 细胞浸润。AuNC@SiO@HA 与抗 PD-1 抗体联合使用可协同抑制肿瘤生长，刺激强烈的 T 淋巴细胞免疫反应。

讨论：AuNC@SiO@HA 介导的 PTT 与抗 PD-1 免疫治疗的联合为肿瘤治疗提出了一种新策略，可有效将免疫“冷”肿瘤转化为“热”肿瘤。