Penetrative biomimetic nanovehicle boosts immunotherapy in triple-negative breast cancer via SOS1 blockade

Abstract

Immunotherapy of triple-negative breast cancer (TNBC) is significantly hindered by the immunosuppressive tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), which constitute the predominant infiltrating immune cell type in TNBC, represent a critical target for "turning off" immunosuppressive TME. Despite numerous ongoing clinical trials, current strategies exhibit limited efficacy in overcoming immunosuppressive TME. Interestingly, regulation of son of sevenless 1 (SOS1), which is overexpressed in TNBC patients, shows promising potential for TAM repolarization. Herein, we developed a biomimetic liposomal platform (CCM/Cil-lipo@TD), which integrates cilengitide (Cil)-functionalized breast cancer cell membranes (CCM) to co-deliver tetrandrine (TET) and low-dose docetaxel (DTX) for TNBC therapy. This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death (ICD)-mediated dendritic cell (DC) maturation, thereby reshaping the highly immunosuppressive TME in TNBC. Critically, the low-density Cil-anchored, CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems, achieving deep intratumoral accumulation of therapeutic payloads. Mechanistically, the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2 (protumor) toward TAM1 (antitumor). Furthermore, SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME, as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells. The CCM/Cil-lipo@TD exerted superior tumor inhibition (82.9%) in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis. Taken together, the Cil-engineered, cell membrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.

Keywords

Son of sevenless 1 / Triple-negative breast cancer / Tetrandrine / Docetaxel / Cilengitide / Liposome

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

We thank the staff members of the Large-scale Protein Preparation System at the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, Chinese Academy of Science, China for providing the Electron Microscopy System technical support and assistance in data collection and analysis. This work was funded by “Shuguang Program”supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission (22SG41), and the combination of the medical care and health project of the Shanghai University of Traditional Chinese Medicine (YYKC-2021–01–008).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2025.101064. The figures and tables with "S" before the serial number are included in the Supplementary material.

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