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<p>Dopamine (DA) has shown antitumor potential and is known to modulate immune responses under physiological conditions; however, its specific immunomodulatory role in cancer immunotherapy remains poorly defined. Triple-negative breast cancer (TNBC) is an aggressive malignancy with strong stemness properties and a limited response to immune checkpoint inhibitors (ICIs). Cancer stem cells (CSCs) contribute significantly to the suppression of the tumor immune microenvironment and immune evasion. However, the ability of DA to remodel the immune microenvironment by targeting CSCs and thereby increasing ICI efficacy in TNBC is not yet understood. To address this, we employed immunocompetent BALB/c mice bearing 4T1 TNBC tumors, performed RNA-seq analysis, and used flow cytometry to assess immune cells in tumors, the spleen, and tumor-draining lymph nodes. These analyses revealed that DA increases cytotoxic T lymphocyte (CTL) levels and activity, with a more pronounced effect observed in local tumor tissues, which indicates that T-cell activation is its primary antitumor mechanism. Using TNBC cell lines (MDA-MB-231, BT549, and 4T1) and CSCs enriched from these cell lines by suspension culture, PD-L1-knockout and D1DR-knockout 4T1 cells, and dopamine receptor (DR) agonists and antagonists, we revealed that the PD-1/PD-L1 pathway predominantly mediates CSC-driven immune evasion, growth, and metastasis in TNBC. Moreover, DA suppresses TNBC CSCs and downregulates PD-L1 expression in these cells specifically through dopamine receptor D1 (D1DR) activation. Furthermore, DA enhances both the antitumor efficacy of CTLs and the intratumoral CTL infiltration induced by a cytotoxic T-lymphocyte-associated protein 4 antibody (αCTLA-4) without compromising safety. DA also inhibits metastasis and prolongs the survival of 4T1 tumor-bearing mice. In conclusion, this study reveals a novel mechanism by which DA regulates tumor immunity in TNBC and demonstrates its novel potential for application in cancer immunotherapy. By investigating the CSC‒PD-L1‒immune axis, we also revealed that anti-CSC therapies are novel, promising ICI synergists for TNBC treatment.</p>

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Dopamine abrogates immunosuppression mediated by PD-L1 of cancer stem cells in a preclinical triple-negative breast cancer model

  • 期刊论文

  • 发表日期：

    2026年4月24日

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  • Jun-sheng Xue,
  • Wei-zhe Jian,
  • Zhu-jun Jiang,
  • Tian-yu Wang,
  • Qi-rui Yang,
  • Qing-yu Yao,
  • Tian-yu Bao,
  • Lei Cai,
  • En-ze Gan,
  • Chen Liu,
  • Tian-yan Zhou

摘要

Dopamine (DA) has shown antitumor potential and is known to modulate immune responses under physiological conditions; however, its specific immunomodulatory role in cancer immunotherapy remains poorly defined. Triple-negative breast cancer (TNBC) is an aggressive malignancy with strong stemness properties and a limited response to immune checkpoint inhibitors (ICIs). Cancer stem cells (CSCs) contribute significantly to the suppression of the tumor immune microenvironment and immune evasion. However, the ability of DA to remodel the immune microenvironment by targeting CSCs and thereby increasing ICI efficacy in TNBC is not yet understood. To address this, we employed immunocompetent BALB/c mice bearing 4T1 TNBC tumors, performed RNA-seq analysis, and used flow cytometry to assess immune cells in tumors, the spleen, and tumor-draining lymph nodes. These analyses revealed that DA increases cytotoxic T lymphocyte (CTL) levels and activity, with a more pronounced effect observed in local tumor tissues, which indicates that T-cell activation is its primary antitumor mechanism. Using TNBC cell lines (MDA-MB-231, BT549, and 4T1) and CSCs enriched from these cell lines by suspension culture, PD-L1-knockout and D1DR-knockout 4T1 cells, and dopamine receptor (DR) agonists and antagonists, we revealed that the PD-1/PD-L1 pathway predominantly mediates CSC-driven immune evasion, growth, and metastasis in TNBC. Moreover, DA suppresses TNBC CSCs and downregulates PD-L1 expression in these cells specifically through dopamine receptor D1 (D1DR) activation. Furthermore, DA enhances both the antitumor efficacy of CTLs and the intratumoral CTL infiltration induced by a cytotoxic T-lymphocyte-associated protein 4 antibody (αCTLA-4) without compromising safety. DA also inhibits metastasis and prolongs the survival of 4T1 tumor-bearing mice. In conclusion, this study reveals a novel mechanism by which DA regulates tumor immunity in TNBC and demonstrates its novel potential for application in cancer immunotherapy. By investigating the CSC‒PD-L1‒immune axis, we also revealed that anti-CSC therapies are novel, promising ICI synergists for TNBC treatment.