Current Status and Future Trends of Cold Atmospheric Plasma as an Oncotherapy

Abstract

Cold atmospheric plasma (CAP), a redox modulation tool, is capable of inhibiting a wide spectrum of cancers and has thus been proposed as an emerging onco-therapy. However, with incremental successes consecutively reported on the anticancer efficacy of CAP, no consensus has been made on the types of tumours sensitive to CAP due to the different intrinsic characteristics of the cells and the heterogeneous design of CAP devices and their parameter configurations. These factors have substantially hindered the clinical use of CAP as an oncotherapy. It is thus imperative to clarify the tumour types responsive to CAP, the experimental models available for CAP-associated investigations, CAP administration strategies and the mechanisms by which CAP exerts its anticancer effects with the aim of identifying important yet less studied areas to accelerate the process of translating CAP into clinical use and fostering the field of plasma oncology.

Keywords: Cancer; Cold atmospheric plasma; Device; Research status; Trends.

Fig. 1

Cancer types and proportions in which cold atmospheric plasma (CAP) is being explored as an oncotherapy. As of 14 December 2022, the field of plasma oncology encompasses eight broad categories of cancer: abdominal organs (45 studies), reproductive organs (44 studies), skin (40 studies), brain (30 studies), bone (18 studies), blood (12 studies), head (9 studies), and soft tissue (2 studies). Breast cancer (‘reproductive organs’), melanoma (‘skin’), glioma (‘brain’), and osteosarcoma (‘bone’) were the most commonly investigated (Table 1).

Fig. 2

Diagram summarizing differences between direct CAP injection and indirect PAM treatment.

Fig. 3

Representative cold atmospheric plasma (CAP) sources. Images and schematic presentations of (A) single electrode DBD, PlasmaDerm^® VU-2010 (CINOGY System GmbH plasma technology, Duderstadt, Germany); (B) plasma jet, kINPen^® (INP Greifswald/neoplas GmbH, Greifswald, Germany); (C) plasma torch, microPlaSterβ^® (Adtec Plasma Technology Co. Ltd., London, UK); and plasma sources for in vivo treatment, i.e., (D) invivoPen and (E) µCAP plasma generator. (A) was reproduced with permission from Bernhardt et al. (2019) under a Creative Commons CC-BY licence; (B) was reproduced with permission from Breathnach et al. (2018) under a Creative Commons CC-BY licence; (C) was reproduced with permission from Arndt et al. (2013a) under a Creative Commons CC-BY licence; (D) was reproduced with permission from Zhou et al. (2020) under a Creative Commons CC-BY licence; and (E) was reproduced with permission from Chen et al. (2017) under a Creative Commons CC-BY licence.

Fig. 4

Effects of cold atmospheric plasma (CAP) on cancer hallmarks. The 10 cancer hallmarks (Senga and Grose, 2021) can be summarized into five traits, i.e., selective triggering of programmed death events in cancer cells, halting of tumour angiogenesis and metastasis, rewiring of tumour metabolism, boosting of immunity and suppression of tumour-promoting inflammation, and accelerated cancer cell genome instability. In response to reactive oxygen and nitrogen species (RONS) induced by CAP, the genome stability of cancer cells is compromised, which accelerates the mutation rate. As the genome integrity of cancer cells is associated with cancer stemness and drug resistance, targeting the integrity of transformed cells often leads to the killing of cancer stem cells and enhanced sensitivity of cancer cells to oncoagents. Cellular RONS levels continue to increase with cell chaos as a result of accelerated genome mutation that, once exceeding the death threshold as sensed by p53 (e.g.), may trigger various types of programmed cell death events. On the other hand, mitochondria, in response to enhanced cellular RONS, may trigger death programs by releasing, e.g., cytochrome C, which activates caspases. CAP can reshape cancer cell metabolism, including that of carbohydrates, nucleic acids, lipids, and amino acids, by redirecting pyruvate from increasing lactate production to enhancing efficient energy production, enabling β-oxidation and disturbing amino acid metabolism. In addition, CAP can promote tumour antigen release, stimulate immunogenic cell death (ICD), enhance tumour antigen presentation by antigen presentation cells, and enhance the sensitivity of tumour cells to immune therapies. Finally, CAP can arrest cancer angiogenesis and metastasis by halting the epithelial-mesenchymal transition (EMT).