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The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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An Endoplasmic Reticulum Stress-Specific Nanoinducer Selectively Evokes Type-II Immunogenic Cell Death for Pyroptotic

Yimeng Zhang1,2,3, Yue Yan4, Jianxiong Liu3

  • 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.

Advanced Materials (Deerfield Beach, Fla.)
|May 28, 2025
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Summary
This summary is machine-generated.

Researchers developed a novel nanoplatform (PCANER) to specifically induce endoplasmic reticulum (ER) stress and type-II immunogenic cell death (ICD) for enhanced cancer immunotherapy.

Keywords:
endoplasmic reticulum stressimmunogenic cell deathimmunotherapypH‐sensitive nanoparticlepyroptosis

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Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cancer Research

Background:

  • Endoplasmic reticulum (ER) stress-initiated type-II immunogenic cell death (ICD) holds promise for cancer immunotherapy.
  • Selective induction of type-II ICD is hindered by inefficient ER targeting strategies.

Purpose of the Study:

  • To develop a pH/Cathepsin-Activatable Nanoplatform (PCAN) for specific photo-induction of ER stress and type-II ICD.
  • To investigate the efficacy of ER-targeted type-II ICD versus lysosome-targeted type-I ICD in cancer therapy.

Main Methods:

  • Designed a dual-gated nanoplatform (PCAN) with long-circulating properties for ER targeting.
  • Evaluated ER targeting efficacy and colocalization in cancer tissues.
  • Assessed the induction of ER stress, type-II ICD, and pyroptosis via glucose-regulated protein 78 and calreticulin exposure.
  • Compared the anti-tumor efficacy of PCANER (ER-targeted) with PCANLy (lysosome-targeted).

Main Results:

  • PCANER demonstrated excellent ER targeting with 83% colocalization in cancer tissues.
  • PCANER effectively intensified ER stress, promoting type-II ICD and pyroptosis, leading to significant immune priming.
  • Lysosome-targeted PCANLy induced mild type-I ICD with negligible anti-tumor effects.
  • The study achieved precise tuning of ICD type and pyroptosis for cancer therapy.

Conclusions:

  • PCAN technology enables spatiotemporal control of subcellular organelle targeting for modulating cell death mechanisms.
  • Targeting ER stress to induce type-II ICD offers a promising strategy for boosting cancer immunotherapy.
  • This work provides new insights into designing organelle-level targeted nanomedicines for cancer treatment.