Cold Physical Plasma in Cancer Therapy: Mechanisms, Signaling, and Immunity

Abstract

Despite recent advances in therapy, cancer still is a devastating and life-threatening disease, motivating novel research lines in oncology. Cold physical plasma, a partially ionized gas, is a new modality in cancer research. Physical plasma produces various physicochemical factors, primarily reactive oxygen and nitrogen species (ROS/RNS), causing cancer cell death when supplied at supraphysiological concentrations. This review outlines the biomedical consequences of plasma treatment in experimental cancer therapy, including cell death modalities. It also summarizes current knowledge on intracellular signaling pathways triggered by plasma treatment to induce cancer cell death. Besides the inactivation of tumor cells, an equally important aspect is the inflammatory context in which cell death occurs to suppress or promote the responses of immune cells. This is mainly governed by the release of damage-associated molecular patterns (DAMPs) to provoke immunogenic cancer cell death (ICD) that, in turn, activates cells of the innate immune system to promote adaptive antitumor immunity. The pivotal role of the immune system in cancer treatment, in general, is highlighted by many clinical trials and success stories on using checkpoint immunotherapy. Hence, the potential of plasma treatment to induce ICD in tumor cells to promote immunity targeting cancer lesions systemically is also discussed.

Figure 1

Schematic of the principles of plasma jets and dielectric barrier discharges (DBD). In plasma jets, the gas flow is required for the generation of cold physical plasma, while the plasma provided by DBD is created in ambient air. Plasma jets are grounded, while many DBD systems use the treatment target as a grounded cathode to produce cold physical plasma. Many types of gases can be used. Usually, noble gases such as argon, helium, and neon are employed, but air ionization is also feasible with specific parameter setups.

Figure 2

The atmospheric pressure argon plasma jet kINPen. The kINPen is a certified medical product in Europe and is regularly employed in dermatology. First initial trials in human cancer patients have been employed. Reproduced from [125].

Figure 3

Model of three cell death signaling pathways in plasma-treated cancer cells. Plasma exposure increases aquaporin transporters in cancer cell membranes that allow the transport of H₂O₂ into the cells. Additionally, plasma treatment oxidizes cellular membranes, leading to cell death signaling. The excessive intracellular ROS contribute to the initiation of the cell death signaling (e.g., apoptosis, autophagy, pyroptosis, and ferroptosis) in cancer cells, partially through the activation of the MAPK pathway.

Figure 4

Model of plasma-induced immunogenic cell death in cancer cells. Plasma exposure leads to an increase in DAMP signaling (e.g., ATP and calreticulin), which (1) provides inflammatory stimuli for (2) promoting the processing of cancer cells by APCs. Consequently, (3) activated APCs promote the development and activation of (4) effector T-cells, capable of precisely and systemically eradicating cancer cells distant from the site of plasma treatment.