Tumor-Repopulating Cell-Derived Microparticle-Based Therapeutics Amplify the Antitumor Effect through Synergistic Inhibition of Chemoresistance and Immune Evasion

  • Mol Pharm. 2025 Feb 3;22(2):733-746. doi: 10.1021/acs.molpharmaceut.4c00709.
Nana Bie  1 ,  Shiyu Li  1 ,  Qingle Liang  1 ,  Wenxia Zheng  1 ,  Shiyi Xu  1 ,  Haojie Liu  1 ,  Xiaojuan Zhang  1 ,  Zhaohan Wei  1 ,  Tuying Yong  1  2  3 ,  Xiangliang Yang  1  2  3 ,  Lu Gan  1  2  3
Affiliations
  • 1. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
  • 2. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
  • 3. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Huazhong University of Science and Technology, Wuhan 430074, China.
PMID: 39772575 DOI: 10.1021/acs.molpharmaceut.4c00709
Abstract

Traditional chemotherapy often encounters failure attributed to drug resistance mediated by tumor-repopulating cells (TRCs) and chemotherapy-triggered immune suppression. The effective inhibition of TRCs and the mitigation of drug-induced immune suppression are pivotal for the successful chemotherapy. Here, TRC-derived microparticles (3D-MPs), characterized by excellent tumor-targeting and high TRC uptake properties, are utilized to deliver metformin and the chemotherapeutic drug doxorubicin ((DOX+Met)@3D-MPs). (DOX+Met)@3D-MPs efficiently enhance tumor accumulation and are highly internalized in tumor cells and TRCs. Additionally, (DOX+Met)@3D-MPs significantly decrease the chemotherapy-triggered upregulation in P-glycoprotein expression to enhance intracellular doxorubicin retention, resulting in increased chemotherapy sensitivity and immunogenic cell death in tumor cells and TRCs for improved antitumor immunity. Importantly, (DOX+Met)@3D-MPs also remarkably reduce chemotherapy-induced PD-L1 expression, efficiently alleviating immune suppression facilitated by the PD-L1/PD-1 axis to further enhance immunological response against malignancy. These results underscore the (DOX+Met)@3D-MPs' potential as a viable platform for augmenting the efficacy of antitumor therapies.

Keywords
cancer treatment; chemoresistance; codelivery; metformin; tumor-repopulating cell-derived microparticles.
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