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Updated: Jan 7, 2026

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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MLKL/retromer axis controls PD-L1 recycling to compromise antitumor immunity during VCP inhibition-induced

Yang Wang1, Zi-Jia Huang1, Nan-Nan Yu1

  • 1Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University, Guangzhou 510632, China.

Proceedings of the National Academy of Sciences of the United States of America
|December 16, 2025
PubMed

Insights

Valosin-containing protein inhibition triggers necroptosis and extracellular vesicle release in colorectal cancer, hindering immunotherapy. Targeting the retromer complex with VCP inhibitors enhances anti-PD-L1 therapy efficacy.

Area of Science:

  • Cancer Biology
  • Immunology
  • Cellular Trafficking

Background:

  • Vesicular trafficking, including endosomal recycling and extracellular vesicle (EV) release, is an adaptive cancer cell mechanism against stress and necroptosis, complicating therapy.
  • The precise mechanisms linking these processes and their impact on cancer immunotherapy remain unclear.

Purpose of the Study:

  • To investigate the role of valosin-containing protein (VCP) inhibition in colorectal cancer (CRC) cell death and immune evasion.
  • To elucidate the molecular mechanisms by which VCP inhibition affects necroptosis, EV release, and programmed death ligand 1 (PD-L1) trafficking.
  • To explore the potential of targeting VCP and the retromer complex for enhancing immunotherapy in CRC.

Main Methods:

  • Utilized VCP inhibition (VCPi) in colorectal cancer models.
  • Performed MLKL knockdown to assess its role in VCPi effects.
  • Investigated the interaction of MLKL, retromer complex, TBC1D5, and Rab7A.
  • Analyzed PD-L1 trafficking and recycling.
  • Evaluated the efficacy of combined VCP inhibition and anti-PD-L1 therapy, with and without retromer complex targeting.

Main Results:

  • VCP inhibition induced EV release and necroptosis in CRC cells, but did not synergize with immunotherapy.
  • VCPi delayed MLKL degradation, and MLKL knockdown reduced VCPi-induced necroptosis, EV release, and PD-L1 recycling.
  • VCPi-induced MLKL accumulation recruited the retromer complex and TBC1D5, inactivating Rab7A and promoting PD-L1 vesicle transport to the cell surface, leading to immunosuppression.
  • Targeting the retromer complex enhanced the efficacy of combined VCP inhibitors and anti-PD-L1 therapy in CRC.

Conclusions:

  • VCP inhibition promotes PD-L1 recycling via MLKL-mediated recruitment of the retromer complex during necroptosis, contributing to immunosuppression in CRC.
  • Dual inhibition of VCP and the retromer complex represents a promising strategy to potentiate immunotherapy efficacy in colorectal cancer.
Keywords:
PD-L1mixed lineage kinase domain-like proteinnecroptosisretromer complexvalosin-containing protein

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