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Combined Photothermal and mTOR-Targeted Therapy Overcomes Immune Evasion and Enhances Checkpoint Blockade Efficacy in Metastatic Triple-Negative Breast Cancer

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机构: [1]Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China. [2]Breast Center, West China Hospital, Sichuan University, Chengdu, 610041, China. [3]Laboratory of pathology, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, China. [4]Research Core Facility, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. [5]Animal Experimental Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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关键词: gold nanosystem immune “cold” tumor immune checkpoint blockade mTOR-targeted therapy photothermal triple-negative breast cancer (TNBC)

摘要:
Triple-negative breast cancer, a representative immune "cold" tumor, resists immune checkpoint blockade (ICB). A promising strategy to overcome this limitation involves combining photothermal therapy (PTT) with ICB. Here, it is demonstrated that while PTT enhances antitumor immunity by inducing immunogenic cell death (ICD), it paradoxically activates the oncogenic mTOR pathway, driving tumor immune evasion. To address this, ASPPR∩A, a mTOR inhibitor-loaded and pH/NIR-II-responsive gold nanocomposite delivering localized hyperthermia and mTOR inhibition, are developed. The nanocomposite selectively targets tumor cells and efficiently converts NIR-II light into hyperthermia upon laser irradiation. In vitro, the nanocomposite-mediated photothermal-mTOR dual-therapy synergistically enhances ICD and MHC-I antigen presentation. In murine TNBC models, this combination significantly amplifies ICD and T-cell infiltration, and synergizes with PD-1 blockade. Notably, this triple-combination regimen effectively eliminates distant metastases via systemic antitumor immune response. The findings reveal the paradoxical role of PTT, establishing a photothermal-targeted-immune combinatorial paradigm for treating metastatic immune "cold" tumors.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.

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出版当年[2025]版:
大类 | 1 区 综合性期刊
小类 | 1 区 化学:综合 1 区 材料科学:综合 1 区 纳米科技
最新[2025]版:
大类 | 1 区 综合性期刊
小类 | 1 区 化学:综合 1 区 材料科学:综合 1 区 纳米科技
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第一作者机构: [1]Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China.
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