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<p>Triple negative breast cancer (TNBC) exhibits an exceptionally low responsiveness to immunotherapy due to its “cold” tumor immune microenvironment. It is urgent to design a rational therapy to reverse “cold” tumors into “hot” ones to improve the therapeutic effects. In this study, we developed a series of immune-activating lipo-polylysine (IAPs), designated as IAP-1 to IAP-9, that display both oncolytic and immunogenic cell death (ICD)-inducing activities. It is confirmed that both oncolytic activity and ICD-inducing capacity of IAPs are structure-dependent. Among them, IAP-4 exhibits the most effective oncolytic and ICD-inducing capabilities in 4T1 tumor cells. Mechanistic investigations suggest that IAP-4 can induce cancer cell necrosis through a membrane-lytic mechanism and trigger potent ICD of tumor cells through membrane lysis and mitochondrial damage. <i>In vivo</i> antitumor activity determination results indicate that IAP-4 effectively converses cold tumors to hot by inducing ICD. This process not only inhibits primary tumors but also elicits specific antitumor immune memory, leading to a significant suppression of tumor recurrence and metastasis. Briefly, this work pioneers a promising drug-free strategy for oncolytic immunotherapy.</p>

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Immune-activating cationic lipo-polypeptides for oncolytic immunotherapy in triple negative breast cancer

  • 期刊论文

  • 发表日期：

    2025年7月15日

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  • Ziwen Gao,
  • Peng Zhang,
  • Renyong Yin,
  • Junqi Wang,
  • Zhihui Guo,
  • Qi Yao,
  • Guowenlie Gao,
  • Xu Huang,
  • Chunsheng Xiao,
  • Yingchao Zhang,
  • Xuesi Chen

摘要

Triple negative breast cancer (TNBC) exhibits an exceptionally low responsiveness to immunotherapy due to its “cold” tumor immune microenvironment. It is urgent to design a rational therapy to reverse “cold” tumors into “hot” ones to improve the therapeutic effects. In this study, we developed a series of immune-activating lipo-polylysine (IAPs), designated as IAP-1 to IAP-9, that display both oncolytic and immunogenic cell death (ICD)-inducing activities. It is confirmed that both oncolytic activity and ICD-inducing capacity of IAPs are structure-dependent. Among them, IAP-4 exhibits the most effective oncolytic and ICD-inducing capabilities in 4T1 tumor cells. Mechanistic investigations suggest that IAP-4 can induce cancer cell necrosis through a membrane-lytic mechanism and trigger potent ICD of tumor cells through membrane lysis and mitochondrial damage. In vivo antitumor activity determination results indicate that IAP-4 effectively converses cold tumors to hot by inducing ICD. This process not only inhibits primary tumors but also elicits specific antitumor immune memory, leading to a significant suppression of tumor recurrence and metastasis. Briefly, this work pioneers a promising drug-free strategy for oncolytic immunotherapy.