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<p>Triple-negative breast cancer (TNBC) is characterized by a highly immunosuppressive tumor microenvironment (TME), which contributes to its poor clinical outcomes. Tumor-associated macrophages (TAMs) constitute a major cellular component of the TME, and the dominance of immunosuppressive M2 phenotype, rather than the pro-inflammatory M1 phenotype, plays a pivotal role in maintaining immune evasion. Reprogramming TAMs from M2 to M1 phenotype represents a promising therapeutic strategy for reversing immunosuppression in TME. In the current study, our findings demonstrated that JQ1, a bromodomain and extra-terminal motif (BET) protein inhibitor, effectively promotes macrophage polarization toward the M1 phenotype both in vitro and in vivo. Furthermore, JQ1 enhances the cytotoxic and phagocytic capacity of TAMs. Mechanistic studies revealed that JQ1 inhibits PPARγ signaling, thereby shifting TAMs toward the M1 phenotype and subsequently promoting T cell-mediated antitumor immunity. Importantly, treatment with JQ1 in combination with anti-CD47 antibody synergistically suppressed 4T1 tumor growth. Our findings uncovered a novel immunomodulatory function of JQ1 in reprogramming TAMs polarization within the TNBC TME and provided a compelling rationale for targeting BET proteins in cancer immunotherapy.</p>

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BET bromodomain inhibition potentiates antitumor activity of tumor-associated macrophages and enhances anti-CD47 immunotherapy in triple-negative breast cancer

  • 期刊论文

  • 发表日期：

    2026年1月10日

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  • Fuxing Mei,
  • Delin Li,
  • Nannan Zhu,
  • Tao Zhu,
  • Han Xie,
  • Yue Liu,
  • Lei Chen,
  • Xiao Zhang,
  • Wei Ji

摘要

Triple-negative breast cancer (TNBC) is characterized by a highly immunosuppressive tumor microenvironment (TME), which contributes to its poor clinical outcomes. Tumor-associated macrophages (TAMs) constitute a major cellular component of the TME, and the dominance of immunosuppressive M2 phenotype, rather than the pro-inflammatory M1 phenotype, plays a pivotal role in maintaining immune evasion. Reprogramming TAMs from M2 to M1 phenotype represents a promising therapeutic strategy for reversing immunosuppression in TME. In the current study, our findings demonstrated that JQ1, a bromodomain and extra-terminal motif (BET) protein inhibitor, effectively promotes macrophage polarization toward the M1 phenotype both in vitro and in vivo. Furthermore, JQ1 enhances the cytotoxic and phagocytic capacity of TAMs. Mechanistic studies revealed that JQ1 inhibits PPARγ signaling, thereby shifting TAMs toward the M1 phenotype and subsequently promoting T cell-mediated antitumor immunity. Importantly, treatment with JQ1 in combination with anti-CD47 antibody synergistically suppressed 4T1 tumor growth. Our findings uncovered a novel immunomodulatory function of JQ1 in reprogramming TAMs polarization within the TNBC TME and provided a compelling rationale for targeting BET proteins in cancer immunotherapy.