2. Academic Validation
  3. C5a/C5aR pathway blocking promoted CuS-mediated cancer therapy effect by inhibiting cuproptosis resistance

C5a/C5aR pathway blocking promoted CuS-mediated cancer therapy effect by inhibiting cuproptosis resistance

  • J Immunother Cancer. 2025 Jun 8;13(6):e011472. doi: 10.1136/jitc-2025-011472.
Hong Yang 1,  Boshao Deng 1,  Xiao Han 1,  Lulu Wang 1,  Jing Zhao 2,  Yunpei Zhao 3,  Zihan Sun 4,  Siyi Wang 1,  Guokang Liu 1,  Yuzhang Wu 5,  Jian Chen 5
Affiliations

Affiliations

  • 1 Department of Immunology, Army Medical University, Chongqing, China.
  • 2 Biomedical Analysis Center, Army Medical University, Chongqing, China.
  • 3 Department of Pharmacy, The Southwest Hospital of AMU, Chongqing, China.
  • 4 Department of breast and thyroid, Guiqian international general hospital, GuiYang, China.
  • 5 Department of Immunology, Army Medical University, Chongqing, China chenjian1@tmmu.edu.cn yuzhangwu@tmmu.edu.cn.
PMID: 40484643 DOI: 10.1136/jitc-2025-011472
Abstract

Background: Breast Cancer is the most diagnosed malignancy and a leading cause of cancer-related deaths among women globally. Cuproptosis plays a significant role in tumor progression and therapeutic response. Increasing studies suggest that targeting Cuproptosis presents a promising strategy for Cancer therapy, such as through the development of copper nanoparticles as therapeutic agents. However, resistance to Cuproptosis has emerged as a critical hallmark of Cancer. Therefore, it is essential to further investigate the mechanisms underlying Cuproptosis resistance to enhance its therapy effect.

Methods: The relationship between breast Cancer progression and the C5a/C5aR pathway or Cuproptosis was determined by single-cell RNA Sequencing analyses, RNA-sequence analyses, bioinformatic analyses, survival analyses and immunohistochemistry. The antitumor effects of CuS nanoparticles and C5a receptor antagonists (C5aRA) were assessed by in vitro and in vivo strategies including cell counting kit-8, colony formation assay, relative Reactive Oxygen Species level assay, western blots, real-time quantitative PCR, immunohistochemistry, immunofluorescence assay, flow cytometry and the xenograft mice models. Complement System activation by CuS nanoparticles was tested by ELISA.

Results: Our results indicated that activation of the C5a/C5aR pathway contributes to Cuproptosis resistance by upregulating ATP7B expression via the Wnt/β-catenin pathway. Consequently, combining CuS nanoparticles with lazer treatment and C5aRA markedly enhanced the antitumor efficacy of CuS nanoparticles by overcoming Cuproptosis resistance, leading to a synergistic effect in Cancer therapy that included cuproptosis-targeting therapy, immunotherapy, and photothermal therapy.

Conclusions: This study reports, for the first time, proved C5a/C5aR pathway-mediated Cuproptosis resistance in Cancer cells, and combining CuS nanoparticles and C5aRA offers a superior and novel therapeutic strategy for Cancer.

Keywords

Breast Cancer; Combination therapy; Complement.

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