Scholarlink

<p>Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited therapeutic efficacy and poor prognosis. To address chemoresistance and immunosuppression in HCC, we developed a lactate-modulating multifunctional prodrug nanocomposite (GD-A NPs). This system is self-assembled from a pentavalent arsenate prodrug (AsO₄³⁻), the hydrogen sulfide (H₂S) donor GYY4137, and the lactate export inhibitor diclofenac (DCF), enabling precise responsiveness to the acidic and reductive tumor microenvironment. Endogenous H₂S selectively reduces intracellular As⁵⁺ to highly cytotoxic As³⁺ in the acidic tumor milieu, thereby activating the prodrug while minimizing systemic toxicity. Simultaneously, H₂S enhances tumor glycolysis-derived lactate production, which, in combination with DCF-mediated inhibition of lactate efflux, leads to intracellular acidification and reversal of the immunosuppressive microenvironment. Excessive lactate accumulation disrupts endoplasmic reticulum (ER) homeostasis, where SERCA2 inhibition depletes ER Ca²⁺ stores and triggers GRP78 dissociation. This event activates PERK-mediated eIF2α phosphorylation and the downstream ATF4/CHOP pathway, ultimately inducing immunogenic cell death (ICD) and promoting systemic immune activation. This is evidenced by the release of damage-associated molecular patterns (DAMPs), dendritic cell maturation, and T cell activation. By integrating lactate metabolism regulation, prodrug activation, and immune remodeling, this strategy provides a promising avenue for combined chemo-immunotherapy of HCC.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Self-activated prodrug nanocomposites reprogramming lactic acid metabolism to initiate acidosis-endoplasmic reticulum stress cascade and potentiate immunogenic cell death for enhanced liver cancer therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月2日

查看全文
  • JingQuan Chen,
  • WeiYi Cheng,
  • WeiYe Ren,
  • LiTing He,
  • Xiaoqi Wang,
  • Xiujuan Hong,
  • ChenLi Wang,
  • Yajun Wu,
  • Dandan Bao,
  • Zhibing Wu,
  • Yinghui Wei,
  • Ji-Gang Piao

摘要

Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited therapeutic efficacy and poor prognosis. To address chemoresistance and immunosuppression in HCC, we developed a lactate-modulating multifunctional prodrug nanocomposite (GD-A NPs). This system is self-assembled from a pentavalent arsenate prodrug (AsO₄³⁻), the hydrogen sulfide (H₂S) donor GYY4137, and the lactate export inhibitor diclofenac (DCF), enabling precise responsiveness to the acidic and reductive tumor microenvironment. Endogenous H₂S selectively reduces intracellular As⁵⁺ to highly cytotoxic As³⁺ in the acidic tumor milieu, thereby activating the prodrug while minimizing systemic toxicity. Simultaneously, H₂S enhances tumor glycolysis-derived lactate production, which, in combination with DCF-mediated inhibition of lactate efflux, leads to intracellular acidification and reversal of the immunosuppressive microenvironment. Excessive lactate accumulation disrupts endoplasmic reticulum (ER) homeostasis, where SERCA2 inhibition depletes ER Ca²⁺ stores and triggers GRP78 dissociation. This event activates PERK-mediated eIF2α phosphorylation and the downstream ATF4/CHOP pathway, ultimately inducing immunogenic cell death (ICD) and promoting systemic immune activation. This is evidenced by the release of damage-associated molecular patterns (DAMPs), dendritic cell maturation, and T cell activation. By integrating lactate metabolism regulation, prodrug activation, and immune remodeling, this strategy provides a promising avenue for combined chemo-immunotherapy of HCC.

Graphical Abstract