A research team led by Associate Professor Yunlu DAI in the University of Macau (UM) Faculty of Health Sciences (FHS) has designed and synthesized a novel nanomedicine, which can convert traditional radiotherapy-mediated apoptosis into pyroptosis, stimulate systemic anti-tumour immune response and significantly inhibit breast cancer growth, recurrence, and metastasis. The research results have been published in the internationally renowned journal Advanced Functional Materials.

Radiotherapy, although clinically effective in in-situ cancer, still cannot radio-functionalise tumours as a potent immunogenetic center. The apoptotic nature induced by radiotherapy limits its activating performance on systemic immunosurveillance. Apoptotic cancer cell maintains its intact membrane that conceals abundant potentially immunogenic damage-associated molecular patterns (DAMPs) inside, the releasing of whom, otherwise, could evoke surrounding immune cells remarkably.

By coordinating natural polyphenols (EGCG) and chemically synthesised polyphenol derivatives with metal ions (W6+), the research team developed a metal-polyphenol coordination nanodrug: PWE, which converts radiotherapy-mediated cell apoptosis to pyroptosis through an epigenetic mechanism, thereby stimulating a systemic anti-tumour immune response. EGCG, functions as a DNA methyltransferase (DNMT) inhibitor, deregulating DNA hypermethylation of tumour cells and recovering their normal expression of the functional GSDME protein which is a key protein of pyroptosis. Noble W6+ sensitised by X-ray radiation boosted cellular ROS production that initiated the activation of caspase-3 through a potential pathway of Bax-Cytochrome c-caspase-9-caspase-3. The activated caspase-3 could be utilised to cleave GSDME upregulated by an EGCG demethylation, generating GSDME-N for cellular membrane perforation. The formed gasdermin pores enable intracellular contents of GSDME, HMGB1, and lactate dehydrogenase (LDH) to pass through and release out of cell, stimulating the immune system and reinvigorating anti-tumour immune responses. To treat the bilateral orthotopic 4T1 breast tumour model with the PWE nanomudulators, the research team identified efficient anti-tumour immune activity, long-lasting immunological memory, and metastatic inhibition. Tumour immunity in traditional radiotherapy is reshaped and ameliorated significantly by epigenetic pyroptosis, which may provide new insights into clinical radiotherapy.

The corresponding author of the related paper is Yunlu DAI, PhD graduate Guohao WANG and Research Assistant Professor Bei LI are the co-first authors. Postdoctoral fellows Lisi XIE and Jie LI, PhD graduates Wei SANG and Zhan ZHANG, PhD students Hao TIAN, Jie YAN, and Wenxi LI also made important contributions to the study. This project is funded by the Science and Technology Development Fund, Macao SAR (file number: 0109/2018/A3, 0011/2019/AKP, 0113/2019/A2, 0103/2021/A, and 0002/2021/AKP), UM (file number: MYRG2022-00011-FHS) and the Shenzhen-Hong Kong-Macau Science and Technology Program (file number:  SGDX20201103093600004). The full text of the research paper can be viewed at: https://onlinelibrary.wiley.com/doi/10.1002/adfm.202213425

Schematic illustration of PWE-relevant preparation and therapeutic strategy.

Guohao WANG (2nd row, third from left), Yunlu DAI (1st row, middle), Bei LI (2nd row, fifth from left)