Trehalose enhanced cold atmospheric plasma-mediated cancer treatment

Xiaona Cao; Tianxu Fang; Mo Chen; Tianqin Ning; Jianyu Li; Peter M Siegel; Morag Park; Zhitong Chen; Guojun Chen

doi:10.1016/j.biomaterials.2024.122582

Trehalose enhanced cold atmospheric plasma-mediated cancer treatment

Biomaterials. 2024 Apr 18:309:122582. doi: 10.1016/j.biomaterials.2024.122582. Online ahead of print.

Authors

Xiaona Cao¹, Tianxu Fang², Mo Chen², Tianqin Ning³, Jianyu Li³, Peter M Siegel⁴, Morag Park⁵, Zhitong Chen⁶, Guojun Chen⁷

Affiliations

¹ Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada; Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada; School of Nursing, Tianjin Medical University, Tianjin, China.
² Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada; Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada.
³ Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada; Department of Mechanical Engineering, McGill University, Montreal, Quebec, Canada.
⁴ Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Quebec, Canada; Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.
⁵ Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada; Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.
⁶ Paul C Lauterbur Research Center for Biomedical Imaging, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China; Advanced Therapeutic Center, National Innovation Center for Advanced Medical Devices, Shenzhen, China.
⁷ Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada; Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. Electronic address: guojun.chen@mcgill.ca.

PMID: 38678699
DOI: 10.1016/j.biomaterials.2024.122582

Abstract

Cold atmospheric plasma (CAP) is a unique form of physical plasma that has shown great potential for cancer therapy. CAP uses ionized gas to induce lethal oxidative stress on cancer cells; however, the efficacy of CAP therapy continues to be improved. Here, we report an injectable hydrogel-mediated approach to enhance the anti-tumor efficacy of CAP by regulating the phosphorylation of eIF2α. We discovered that reactive oxygen and nitrogen species (ROS/RNS), two main anti-tumor components in CAP, can lead to lethal oxidative stress on tumor cells. Elevated oxidative stress subsequently induces eIF2α phosphorylation, a pathognomonic marker of immunogenic cell death (ICD). Trehalose, a natural disaccharide sugar, can further enhance CAP-induced ICD by elevating the phosphorylation of eIF2α. Moreover, injectable hydrogel-mediated delivery of CAP/trehalose treatment promoted dendritic cell (DC) maturation, initiating tumor-specific T-cell mediated anti-tumor immune responses. The combination therapy also supported the polarization of tumor-associated macrophages to an M1-like phenotype, reversing the immunosuppressive tumor microenvironment and promoting tumor antigen presentation to T cells. In combination with immune checkpoint inhibitors (i.e., anti-programmed cell death protein 1 antibody, aPD1), CAP/trehalose therapy further inhibited tumor growth. Importantly, our findings also indicated that this hydrogel-mediated local combination therapy engaged the host systemic innate and adaptive immune systems to impair the growth of distant tumors.

Keywords: Cold atmospheric plasma; Drug delivery; Immune checkpoint blockade; Immunogenic cell death; Injectable hydrogel; eIF2α phosphorylation.