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Updated: Dec 9, 2025
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Recombinant viruses delivering the necroptosis mediator MLKL induce a potent antitumor immunity in mice
Lien Van Hoecke1,2, Stephanie Riederer3, Xavier Saelens1,2,4
1VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
Abstract:
Vaccinia viruses (VACV) are a novel class of immune-oncolytic therapeutics and their mechanism of action is based both on their capacity to replicate selectively in cancer cells and to elicit danger signals that can boost anti-tumor immunity. We recently reported that the intratumor expression of MLKL, a necroptosis inducing factor, generates a protective anti-tumor immunity. Here, we combined both approaches to test the use of VACV to deliver MLKL into the tumor. We generated VACV vectors expressing MLKL and evaluated the effects of MLKL on antitumor efficacy. In vitro infection of cancer cells with MLKL-expressing vectors led to cell death with necroptotic hallmarks. In syngeneic mouse tumor models, VACV expressing MLKL induced an outstanding antitumor activity, which was associated with a robust immunity directed against neo-epitopes. In conclusion, delivery of MLKL by VACV vectors boosts the intrinsic anti-tumor properties of these viral vectors by promoting in situ immunogenic cell death of infected cancer cells.
Insights
Vaccinia virus (VACV) vectors engineered to express MLKL enhance anti-tumor immunity. This combination promotes immunogenic cell death in cancer cells, boosting therapeutic efficacy.
Area of Science:
- Oncolytic virotherapy
- Cancer immunology
- Molecular and cell biology
Background:
- Vaccinia viruses (VACV) are immune-oncolytic therapeutics that replicate in cancer cells and stimulate anti-tumor immunity.
- Intratumoral MLKL expression has been shown to induce protective anti-tumor immunity.
Purpose of the Study:
- To investigate the combined therapeutic potential of VACV vectors delivering MLKL into tumors.
- To evaluate the impact of MLKL expression on VACV-mediated anti-tumor efficacy and immune response.
Main Methods:
- Generation of VACV vectors engineered to express MLKL.
- In vitro assessment of MLKL-expressing VACV on cancer cell death.
- Evaluation of anti-tumor activity and immune response in syngeneic mouse tumor models.
Main Results:
- MLKL-expressing VACV vectors induced cancer cell death with necroptotic characteristics in vitro.
- VACV-MLKL demonstrated significant anti-tumor activity in mouse models.
- The enhanced efficacy was correlated with a strong immune response against tumor neo-epitopes.
Conclusions:
- VACV vectors expressing MLKL significantly boost anti-tumor immunity.
- This approach promotes in situ immunogenic cell death of cancer cells.
- Combining VACV with MLKL delivery represents a promising strategy for cancer immunotherapy.
