2. Academic Validation
  3. NGR-modified curcumin nanovesicles reverse immunotherapy resistance in triple-negative breast cancer via TLR9 and mTOR pathway modulation

NGR-modified curcumin nanovesicles reverse immunotherapy resistance in triple-negative breast cancer via TLR9 and mTOR pathway modulation

  • Cell Biol Toxicol. 2025 Jul 1;41(1):109. doi: 10.1007/s10565-025-10055-1.
Shuo Wang # 1,  Xiaoou Wang # 2,  Xinyu Zheng 1 3,  Haiyang Jiang 1,  Lu Liu 1,  Ningye Ma 4,  Xiaoshen Dong 5
Affiliations

Affiliations

  • 1 Department of Surgical Oncology, Breast Surgery, General Surgery, The First Hospital of China Medical University, Shenyang, China.
  • 2 Department of Geriatric Cardiovascular, The First Hospital of China Medical University, Shenyang, China.
  • 3 Lab 1, Cancer Institute, The First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 4 Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. maningyehead@163.com.
  • 5 Department of Surgical Oncology, Breast Surgery, General Surgery, The First Hospital of China Medical University, Shenyang, China. dongx_cmu1h@163.com.
  • # Contributed equally.
PMID: 40590998 DOI: 10.1007/s10565-025-10055-1
Abstract

Curcumin (Cur), a natural bioactive compound extracted from Curcuma longa, has garnered extensive interest due to its modulation of inflammation, antioxidant, and anti-tumor properties. However, its therapeutic translation remains constrained by limited systemic bioavailability. Triple-negative breast Cancer (TNBC), an aggressive variant of breast malignancies, exhibits strong resistance to conventional therapies and poor prognosis. The present study was designed to clarify the mechanism through which NGR-modified nanovesicles loaded with Cur (NGR-NVs@Cur) reverse immunotherapy resistance in TNBC. Using transcriptomic and network pharmacology analysis, we identified key genes involved in TNBC development and immunotherapy resistance to determine the targets of Cur. In vitro experiments, including SA-β-gal staining, flow cytometry, and glycolysis analysis, validated that TNBC cells induce glycolysis and CD8+ T cell senescence. NGR-NVs@Cur were successfully constructed and marked by transmission electron microscopy (TEM), dynamic light scattering (DLS), pH-responsive release, and cellular uptake assays. Further cell-based studies demonstrated that NGR-NVs@Cur suppressed TNBC cell proliferation, migration, glycolysis, and reversed CD8+ T cell senescence. In vivo, both subcutaneous xenograft and adoptive T cell transfer models were developed to evaluate the therapeutic effects of NGR-NVs@Cur in combination with immune checkpoint inhibitors (ICIs, e.g., J43). The results revealed that Cur inhibited TNBC cell glycolysis and T cell senescence by activating TLR9 and suppressing the mTOR pathway, and that NGR-NVs@Cur enhanced targeted Cur delivery and effectively reversed immunotherapy resistance. This study demonstrated a novel strategy by which Cur, delivered via tumor-targeted nanovesicles, modulates glycolysis and CD8+ T cell senescence through the TLR9-mTOR axis, offering promising insights into overcoming immune resistance in TNBC.

Keywords

Curcumin; Immunotherapy Resistance; MTOR; Nanovesicles; TLR9; Triple-Negative Breast Cancer.

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