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<p>Dysregulated metabolism and functions of immune cells in the tumor microenvironment (TME) are key factors contributing to cancer progression. As the core immune cells in TME, tumor-associated macrophages (TAMs) have become a central focus in metabolic research of TME, though underlying mechanisms are not fully elucidated. Here, we found that long-chain acyl-coenzyme A synthetase-3 (ACSL3) is highly expressed in TAMs and correlates with poor prognosis in colorectal cancer (CRC). ACSL3 depletion induces TAM ferroptosis and reprograms them toward an M1-like phenotype. We further revealed that ACSL3 undergoes lactylation in TAMs, and identified Sirtuin 7 (SIRT7) as its delactylase. Mechanistically, SIRT7 delactylates ACSL3 at lysine 679, restores its enzymatic function and reprograms lipid metabolism in TAMs. Importantly, lactylated and activated ACSL3 significantly protects TAMs from ferroptotic stress and sustains their immunosuppressive phenotype. On the contrary, inhibiting ACSL3 lactylation reprograms TAMs toward an M1-like phenotype, further restores T cell cytotoxicity and suppresses CRC progression. Collectively, these findings establish ACSL3 lactylation in TAMs as a crucial signaling event that enables ferroptosis resistance and maintains M2 polarization, thereby promoting CRC progression. This study provides the therapeutic potential of targeting SIRT7-mediated delactylation of ACSL3 in TAMs, offering a promising strategy for CRC therapy.</p>

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SIRT7-mediated ACSL3 delactylation suppresses colorectal cancer progression by orchestrating tumor-associated macrophage ferroptosis and polarization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Lingzhen Jiang,
  • Chaoqun Li,
  • Peng Teng,
  • Yan Qin,
  • Junhui Tang,
  • Xiaohui Hu,
  • Yuna Li,
  • Feiyu Qin,
  • Surui Yao,
  • Xiaowei Qi,
  • Zhaohui Huang,
  • Yuan Yin

摘要

Dysregulated metabolism and functions of immune cells in the tumor microenvironment (TME) are key factors contributing to cancer progression. As the core immune cells in TME, tumor-associated macrophages (TAMs) have become a central focus in metabolic research of TME, though underlying mechanisms are not fully elucidated. Here, we found that long-chain acyl-coenzyme A synthetase-3 (ACSL3) is highly expressed in TAMs and correlates with poor prognosis in colorectal cancer (CRC). ACSL3 depletion induces TAM ferroptosis and reprograms them toward an M1-like phenotype. We further revealed that ACSL3 undergoes lactylation in TAMs, and identified Sirtuin 7 (SIRT7) as its delactylase. Mechanistically, SIRT7 delactylates ACSL3 at lysine 679, restores its enzymatic function and reprograms lipid metabolism in TAMs. Importantly, lactylated and activated ACSL3 significantly protects TAMs from ferroptotic stress and sustains their immunosuppressive phenotype. On the contrary, inhibiting ACSL3 lactylation reprograms TAMs toward an M1-like phenotype, further restores T cell cytotoxicity and suppresses CRC progression. Collectively, these findings establish ACSL3 lactylation in TAMs as a crucial signaling event that enables ferroptosis resistance and maintains M2 polarization, thereby promoting CRC progression. This study provides the therapeutic potential of targeting SIRT7-mediated delactylation of ACSL3 in TAMs, offering a promising strategy for CRC therapy.