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<p>The immunosuppressive tumor microenvironment (TME) is a pivotal contributor to therapeutic resistance in triple-negative breast cancer (TNBC). Immunogenic cell death (ICD), which activates antitumor immunity through damage-associated molecular pattern (DAMP) release, represents a promising therapeutic strategy for TNBC. Although gambogic acid (GA) triggers ICD by inducing synergistic apoptosis/ferroptosis and DAMP secretion, its clinical translation is hindered by non-specific targeting, poor solubility, and systemic toxicity. To overcome these limitations, we engineered homologous tumor cell membrane-coated GA/Ga³⁺ nanoparticles (M@GAGa NPs) that operate through a triple-functionality: (1) Tumor-targeted delivery: Homologous membrane coating enables immune evasion and precise TNBC tissue accumulation. (2) TME-responsive synergy: Acidic TME-triggered release of GA and Ga³⁺ permits Ga³⁺-mediated disruption of tumor metabolism via ferric ion mimicry, synergistically enhancing GA-induced cytotoxicity. (3) Immunomodulation: GA-induced ICD releases immune signalling molecules such as calreticulin (CRT) and high mobility group protein B1 (HMGB1), while Ga³⁺ reprograms immunosuppressive cells, collectively activating dendritic cell (DC) antigen presentation and CD8⁺ T cell-mediated antitumor immunity. M@GAGa NPs remodel the immunosuppressive TNBC microenvironment through multimodal synergy, offering an innovative precision immunotherapy platform to overcome current therapeutic constraints.</p>

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Synergistic gambogic acid/Ga³⁺ remodels the immunosuppressive tumor microenvironment to enhance triple-negative breast cancer therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月11日

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  • Chong Qiu,
  • Pengbo Guo,
  • Chen Wang,
  • Qingchao Tu,
  • LinYing Zhong,
  • Yuanfeng Fu,
  • Yinan Liu,
  • Huanhuan Pang,
  • Yuqing Meng,
  • Qiaoli Shi,
  • Junzhe Zhang,
  • Fei Xia,
  • Jigang Wang

摘要

The immunosuppressive tumor microenvironment (TME) is a pivotal contributor to therapeutic resistance in triple-negative breast cancer (TNBC). Immunogenic cell death (ICD), which activates antitumor immunity through damage-associated molecular pattern (DAMP) release, represents a promising therapeutic strategy for TNBC. Although gambogic acid (GA) triggers ICD by inducing synergistic apoptosis/ferroptosis and DAMP secretion, its clinical translation is hindered by non-specific targeting, poor solubility, and systemic toxicity. To overcome these limitations, we engineered homologous tumor cell membrane-coated GA/Ga³⁺ nanoparticles (M@GAGa NPs) that operate through a triple-functionality: (1) Tumor-targeted delivery: Homologous membrane coating enables immune evasion and precise TNBC tissue accumulation. (2) TME-responsive synergy: Acidic TME-triggered release of GA and Ga³⁺ permits Ga³⁺-mediated disruption of tumor metabolism via ferric ion mimicry, synergistically enhancing GA-induced cytotoxicity. (3) Immunomodulation: GA-induced ICD releases immune signalling molecules such as calreticulin (CRT) and high mobility group protein B1 (HMGB1), while Ga³⁺ reprograms immunosuppressive cells, collectively activating dendritic cell (DC) antigen presentation and CD8⁺ T cell-mediated antitumor immunity. M@GAGa NPs remodel the immunosuppressive TNBC microenvironment through multimodal synergy, offering an innovative precision immunotherapy platform to overcome current therapeutic constraints.