2. Academic Validation
  3. TME-responsive nanoparticles co-targeting VCP, NETs, and dual immune checkpoints for immune revitalization in EGFR/PD-L1/CTLA-4-driven colorectal cancer

TME-responsive nanoparticles co-targeting VCP, NETs, and dual immune checkpoints for immune revitalization in EGFR/PD-L1/CTLA-4-driven colorectal cancer

  • Biomed Pharmacother. 2025 Sep 18:192:118565. doi: 10.1016/j.biopha.2025.118565.
Yu-Li Lo 1,  Hua-Ching Lin 2,  Yaorong Lee 3,  Hui-Yen Chuang 4,  Tsui-Fen Chou 5
Affiliations

Affiliations

  • 1 Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Faculty of Pharmacy, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; Research Fellow, Taipei Veterans General Hospital, Taiwan. Electronic address: yulilo@nycu.edu.tw.
  • 2 Division of Colorectal Surgery, Cheng Hsin General Hospital, Taipei, Taiwan; Department of Healthcare Information and Management, Ming Chuan University, Taoyuan, Taiwan.
  • 3 Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
  • 4 Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
  • 5 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States; Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91125, United States.
PMID: 40972397 DOI: 10.1016/j.biopha.2025.118565
Abstract

Colorectal Cancer (CRC) remains a formidable clinical challenge due to immune escape, metastasis, and resistance to conventional therapies. This study engineered a tumor microenvironment (TME)-responsive platform of orthogonally masked polyethylene glycol (omPEG)-coated solid lipid nanoparticles (SLNs) for targeted combinatorial immunotherapy in EGFR/PD-L1/CTLA-4-dysregulated CRC. The formulation co-delivered NMS-873 (NM), a VCP/p97 Inhibitor, to induce endoplasmic reticulum stress (ERS) and proteostasis collapse, together with bispecific PD-L1/CTLA-4 Aptamers (P1C4) for dual checkpoint blockade. A complementary SLN formulation encapsulating galunisertib (G) and DNase (DN) degraded neutrophil extracellular traps (NETs) and suppressed tumor-associated neutrophils (TANs), thereby reshaping the immunosuppressive TME. The pH-sensitive omPEG shell preserved peptide ligand activity in circulation and enabled tumor-localized exposure of moieties targeting EGFR, ER, PD-L1, and CXCR2, thereby directing delivery toward CRC cells, tumor-associated macrophages (TAMs), and TANs. NM-induced ERS led to immunogenic cell death, G1 arrest, and Apoptosis, while P1C4 co-loading suppressed epithelial-mesenchymal transition (EMT) and Cancer stem cell (CSC)-like traits by downregulating N-Cadherin/Slug/Snail/Smad and CD44/Oct4/Nanog/c-Myc/MMP-9 and restoring E-cadherin, thereby mitigating tumor migration and aggressiveness. The combinatorial treatment provoked potent antitumor immunity, reactivated dendritic and CD8⁺/CD4⁺ T cells, and enhanced proinflammatory cytokines (IL-1α, IL-2, IL-9, IL-12, IFN-γ, TNF-α, MIP-1β), while suppressing TGF-β, IL-4, IL-5, IL-10, Tregs, TAMs, and TANs. In vivo PET/MRI imaging and immunohistopathological analyses confirmed selective tumor accumulation and effective tumor regression. This peptide-guided, TME-tailored SLN strategy achieves coordinated immune reprogramming, ERS induction, EMT/CSC reversal, NET disruption, and dual checkpoint blockade, offering a clinically translatable platform to overcome chemoimmunotherapy resistance in EGFR/PD-L1/CTLA-4-driven CRC.

Keywords

Colorectal cancer (CRC); Endoplasmic reticulum stress; Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs); Immune checkpoint blockade; Nanoparticle drug delivery; Neutrophil extracellular traps (NETs).

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