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

作者：Chong Qiu, Pengbo Guo, Chen Wang, Qingchao Tu, Lin Zhong, Yuanfeng Fu, Yinan Liu, Huanhuan Pang, Yuqing Meng, Qiaoli Shi, Junzhe Zhang, Fei Xia, Jigang Wang · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03758-4 · 被引用次数：11 · 研究领域：Natural Compound Pharmacology Studies、Nanoplatforms for cancer theranostics、Immune cells in cancer

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 const...