Deng Wen, Chen Yuan, Bai Yongke, Shang Haojie, Wu Jian, Zhong Zichen, Ba Xiaozhuo, Tong Yonghua, He Yu, Jiang Kehua, Tang Kun
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Nanobiotechnology. 2025 Jun 7;23(1):425. doi: 10.1186/s12951-025-03511-x.
Immunotherapy has become a promising and transformative approach for treating advanced or treatment-resistant bladder cancer (BCa). However, its efficacy remains limited due to the immunosuppressive tumor microenvironment (TME) and insufficient immune cell infiltration. Photothermal therapy (PTT), which could cause immunogenic cell death (ICD) in tumor tissue, has been explored as a synergistic approach for bladder cancer immunotherapy. Yet, thermal resistance in cancer cells often undermines the effectiveness of PTT. To address these challenges, we proposed a novel strategy that combines PTT with cuproptosis, a recently identified form of ICD, by engineering Tim-3-overexpressing T cell membrane-coated nanoparticles (Tim3@PHSM@IC) to enhance BCa immunotherapy. The overexpression of Tim-3 on the T cell membrane enabled precise targeting of tumor cells and competitively inhibited the Tim-3 receptor on T cells through recognition of Galectin-9. In vitro, Tim3@PHSM@IC nanoparticles effectively induced photothermal cytotoxicity and robust cuproptosis. In vivo, these nanoparticles significantly inhibited tumor growth in multiple BCa mouse models. Flow cytometry (FCM) and RNA sequencing (RNA-seq) analyses revealed that Tim3@PHSM@IC nanoparticles reprogrammed the TME by activating immune-related genes and enhancing ICD This study highlights the potential of Tim3@PHSM@IC nanoparticles in overcoming the immunosuppressive TME and improving the efficacy of BCa immunotherapy by integrating PTT and cuproptosis.
免疫疗法已成为治疗晚期或难治性膀胱癌(BCa)的一种有前景且具有变革性的方法。然而,由于免疫抑制性肿瘤微环境(TME)和免疫细胞浸润不足,其疗效仍然有限。光热疗法(PTT)可在肿瘤组织中引发免疫原性细胞死亡(ICD),已被探索作为膀胱癌免疫疗法的一种协同方法。然而,癌细胞中的热抗性常常会削弱PTT的有效性。为应对这些挑战,我们提出了一种新策略,即通过构建过表达Tim-3的T细胞膜包覆纳米颗粒(Tim3@PHSM@IC),将PTT与铜死亡(一种最近发现的ICD形式)相结合,以增强BCa免疫疗法。T细胞膜上Tim-3的过表达能够精准靶向肿瘤细胞,并通过识别半乳糖凝集素-9竞争性抑制T细胞上的Tim-3受体。在体外,Tim3@PHSM@IC纳米颗粒有效诱导光热细胞毒性和强烈的铜死亡。在体内,这些纳米颗粒在多个BCa小鼠模型中显著抑制肿瘤生长。流式细胞术(FCM)和RNA测序(RNA-seq)分析表明,Tim3@PHSM@IC纳米颗粒通过激活免疫相关基因和增强ICD对TME进行了重编程。本研究突出了Tim3@PHSM@IC纳米颗粒在克服免疫抑制性TME以及通过整合PTT和铜死亡提高BCa免疫疗法疗效方面的潜力。
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