Li Lin, Zhang Mengxing, Liu Tiantian, Li Jing, Sun Shili, Chen Junjie, Liu Zhenmi, Zhang Zhirong, Zhang Ling
Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
Med-X center for Materials, College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China.
Acta Biomater. 2022 Dec;154:454-466. doi: 10.1016/j.actbio.2022.10.008. Epub 2022 Oct 12.
Photothermal therapy (PTT) was reported to induce synergistic immunogenic cell death (ICD) which may convert tumor cells into "therapeutic vaccines". However, this is often insufficient to prevent tumor recurrence, in part because of the immunosuppressive microenvironment in tumors. Therefore, remodeling tumor microenvironment is of great importance to enhance the therapeutic efficacy of PTT. We herein fabricated a versatile nano-photosensitizer by assembling quercetin and Ferrum ion (QFN). The released quercetin from QFN could reduce programmed death ligand 1 (PD-L1) in tumor cells by inhibiting the phosphorylation of JAK2 and STAT3, and reshape extracellular matrix (ECM) by down-regulating α-SMA fibroblast in tumors. Moreover, QFN could capture tumor antigen and deliver it to the tumor-draining lymph nodes after PTT, which further enhanced the activation of antigen-presenting cells. As a result, QFN-based PTT eliminated melanoma and induced long-term immune memory to prevent tumor metastasis and recurrence. This study provides an effective and translationally feasible photothermic agent for photothermal/immunotherapy. STATEMENT OF SIGNIFICANCE: The efficacy of photothermal therapy (PTT) in cancer treatment is often limited by the immunosuppressive microenvironment in tumors. Herein, we prepared a versatile photosensitizer by assembling quercetin and Ferrum ion (QFN). Upon near-infrared light irradiation, QFN-PTT induced cancer cells destruction and tumor antigen release. QFN then captured antigen and delivered it to the tumor-draining lymph nodes, thus promoting dendritic cell maturation and T cells activation. Quercetin released from QFN in tumors improved T cells infiltration and activation in tumor by regulating immunosuppressive microenvironment. The QFN-PTT-treated mice exhibited significantly elongated survival time, and gained strong anti-tumor immune memory to prevent tumor metastasis and recurrence. Thus, this work provided a simple and versatile photothermic agent, and it has important implications for designing effective and translationally feasible photosensitizers for PTT.
据报道，光热疗法（PTT）可诱导协同免疫原性细胞死亡（ICD），这可能会将肿瘤细胞转化为“治疗性疫苗”。然而，这往往不足以防止肿瘤复发，部分原因是肿瘤中的免疫抑制微环境。因此，重塑肿瘤微环境对于提高PTT的治疗效果至关重要。我们在此通过组装槲皮素和铁离子（QFN）制备了一种多功能纳米光敏剂。从QFN释放的槲皮素可通过抑制JAK2和STAT3的磷酸化来降低肿瘤细胞中的程序性死亡配体1（PD-L1），并通过下调肿瘤中的α-SMA成纤维细胞来重塑细胞外基质（ECM）。此外，QFN可捕获肿瘤抗原并在PTT后将其递送至肿瘤引流淋巴结，这进一步增强了抗原呈递细胞的活化。结果，基于QFN的PTT消除了黑色素瘤并诱导了长期免疫记忆以防止肿瘤转移和复发。本研究为光热/免疫治疗提供了一种有效且具有转化可行性的光热剂。意义声明：光热疗法（PTT）在癌症治疗中的疗效通常受到肿瘤中免疫抑制微环境的限制。在此，我们通过组装槲皮素和铁离子（QFN）制备了一种多功能光敏剂。在近红外光照射下，QFN-PTT诱导癌细胞破坏和肿瘤抗原释放。然后QFN捕获抗原并将其递送至肿瘤引流淋巴结，从而促进树突状细胞成熟和T细胞活化。肿瘤中从QFN释放的槲皮素通过调节免疫抑制微环境改善了肿瘤中T细胞的浸润和活化。经QFN-PTT治疗的小鼠存活时间显著延长，并获得了强大的抗肿瘤免疫记忆以防止肿瘤转移和复发。因此，这项工作提供了一种简单且多功能的光热剂，并且对于设计用于PTT的有效且具有转化可行性的光敏剂具有重要意义。
