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，这种方案的临床益处仍然有限，特别是在缺乏浸润 T 细胞的肿瘤（称为“冷”肿瘤）中。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，改善了实体瘤消融的效果。因此，PTT和ICB的联合治疗对于“冷”肿瘤患者来说是一种有前途的治疗方案。第二种近红外（NIR-II）光激活金纳米复合材料AuNC@SiO2@HA，以AuNC为内核，二氧化硅为壳，合成了用于PTT的透明质酸（HA）聚合物作为靶向分子。制备的 AuNC@SiO2@HA 纳米复合材料进行了各种体外研究，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。使用免疫“冷”黑色素瘤小鼠模型评估了 AuNC@SiO2@HA 介导的 PTT 和抗 PD-1 免疫疗法的协同效应。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 ICD 相关标记物（包括 HSP70、CRT 和 HMGB1）的免疫化学染色研究了 AuNC@SiO2@HA 诱导 T 细胞浸润的机制。最后对AuNC@SiO2@HA纳米复合材料的体内安全性进行了评价。成功合成了吸收范围覆盖1064 nm的AuNC@SiO2@HA纳米复合材料。该纳米系统可以有效地递送到肿瘤细胞内，在激光照射下将光能转化为热能，并在体外诱导肿瘤细胞凋亡。在体内小鼠黑色素瘤模型中，AuNC@SiO2@HA 纳米复合材料显着诱导 ICD 和 T 细胞浸润。 AuNC@SiO2@HA和抗PD-1抗体的组合通过刺激强大的T淋巴细胞免疫反应协同抑制肿瘤生长。AuNC@SiO2@HA介导的PTT和抗PD-1免疫疗法的组合提出了一种新的策略肿瘤治疗，有效地将免疫“冷”肿瘤转化为“热”肿瘤。版权所有 © 2023 肖、赵、王、曾、罗和静。

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.A second near-infrared (NIR-II) light-activated gold nanocomposite AuNC@SiO2@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@SiO2@HA nanocomposites underwent various in vitro studies to characterize their physicochemical properties, light absorption spectra, photothermal conversion ability, cellular uptake ability, and bioactivities. The synergistic effect of AuNC@SiO2@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@SiO2@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@SiO2@HA nanocomposites was evaluated in vivo.The AuNC@SiO2@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 vitro. In an in vivo mouse melanoma model, AuNC@SiO2@HA nanocomposites significantly induced ICD and T-cell infiltration. The combination of AuNC@SiO2@HA and anti-PD-1 antibody synergistically inhibited tumor growth via stimulating robust T lymphocyte immune responses.The combination of AuNC@SiO2@HA-mediated PTT and anti-PD-1 immunotherapy proposed a neoteric strategy for oncotherapy, which efficiently convert the immune "cold" tumors into "hot" ones.Copyright © 2023 Xiao, Zhao, Wang, Zeng, Luo and Jing.