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Breast cancer (BC) and oral squamous cell carcinoma (OSCC) are among the most common types of cancer, but current clinical outcomes remain unsatisfactory. Available therapies have limitations in terms of efficacy and may also cause severe side effects. Cold physical plasma is a promising approach for selectively eliminating cancer cells while avoiding genotoxic effects on non-malignant cells. In this study, we investigated the potential of cold physical plasma as a therapeutic intervention for BC and OSCC through in vitro and ex vivo studies on toxicity. For the in vitro study, T-47 BC cells and SCC-4 and SCC-9 OSCC cell lines were used, and we found cold plasma to be toxic in a treatment time-dependent manner. Moreover, we investigated the safety of physical plasma therapy and found no genotoxic potential in plasma-treated human keratinocytes in vitro. Finally, for the first time, 20 BC and OSCC patient-derived tumor tissues were punch biopsied and ex vivo-exposed to cold physical plasmas to study responses in the tumor microenvironment TME). Cold physical plasma caused significant apoptosis in patient-derived BC and OSCC tumor tissues, and decreased the number of CD163+ cells (e.g., tumor-associated macrophages, TAM) in BC tissue plasma-treated ex vivo. Collectively, our findings motivate the investigation of cold physical plasma as a potential adjuvant treatment in oncology. [ABSTRACT FROM AUTHOR]

Despite therapeutic improvements in recent years, breast cancer remains an often fatal disease. In addition, breast cancer ulceration may occur during late stages, further complicating therapeutic or palliative interventions. In the past decade, a novel technology received significant attention in the medical field: gas plasma. This topical treatment relies on the partial ionization of gases that simultaneously produce a plethora of reactive oxygen and nitrogen species (ROS/RNS). Such local ROS/RNS overload inactivates tumour cells in a non‐necrotic manner and was recently identified to induce immunogenic cancer cell death (ICD). ICD promotes dendritic cell maturation and amplifies antitumour immunity capable of targeting breast cancer metastases. Gas plasma technology was also shown to provide additive toxicity in combination with radio and chemotherapy and re‐sensitized drug‐resistant breast cancer cells. This work outlines the assets of gas plasma technology as a novel tool for targeting breast cancer by summarizing the action of plasma devices, the roles of ROS, signalling pathways, modes of cell death, combination therapies and immunological consequences of gas plasma exposure in breast cancer cells in vitro, in vivo, and in patient‐derived microtissues ex vivo. [ABSTRACT FROM AUTHOR]

Recent research indicated the potential of cold physical plasma in cancer therapy. The plethora of plasma-derived reactive oxygen and nitrogen species (ROS/RNS) mediate diverse antitumor effects after eliciting oxidative stress in cancer cells. We aimed at exploiting this principle using a newly designed dual-jet neon plasma source (Vjet) to treat colorectal cancer cells. A treatment time-dependent ROS/RNS generation induced oxidation, growth retardation, and cell death within 3D tumor spheroids were found. In TUM-CAM, a semi in vivo model, the Vjet markedly reduced vascularized tumors' growth, but an increase of tumor cell immunogenicity or uptake by dendritic cells was not observed. By comparison, the argon-driven single jet kINPen, known to mediate anticancer effects in vitro, in vivo, and in patients, generated less ROS/RNS and terminal cell death in spheroids. In the TUM-CAM model, however, the kINPen was equivalently effective and induced a stronger expression of immunogenic cancer cell death (ICD) markers, leading to increased phagocytosis of kINPen but not Vjet plasma-treated tumor cells by dendritic cells. Moreover, the Vjet was characterized according to the requirements of the DIN-SPEC 91315. Our results highlight the plasma device-specific action on cancer cells for evaluating optimal discharges for plasma cancer treatment. [ABSTRACT FROM AUTHOR]

Plasma medicine is gaining increasing attention and is moving from basic research into clinical practice. While areas of application are diverse, much research has been conducted assessing the use of cold atmospheric pressure plasma (CAP) in wound healing and cancer treatment—two applications with entirely different goals. In wound healing, a tissue-stimulating effect is intended, whereas cancer therapy aims at killing malignant cells. In this review, we provide an overview of the latest clinical and some preclinical research on the efficacy of CAP in wound healing and cancer therapy. Furthermore, we discuss the current understanding of molecular signaling mechanisms triggered by CAP that grant CAP its antiseptic and tissue regenerating or anti-proliferative and cell death-inducing properties. For the efficacy of CAP in wound healing, already substantial evidence from clinical studies is available, while evidence for therapeutic effects of CAP in oncology is mainly from in vitro and in vivo animal studies. Efforts to elucidate the mode of action of CAP suggest that different components, such as ultraviolet (UV) radiation, electromagnetic fields, and reactive species, may act synergistically, with reactive species being regarded as the major effector by modulating complex and concentration-dependent redox signaling pathways. [ABSTRACT FROM AUTHOR]

Plasma medicine is an innovative research field combining plasma physics, life science, and clinical medicine. It is mainly focused on the application cold atmospheric plasma (CAP) in therapeutic settings. Based on its ability to inactivate microorganisms but also to stimulate tissue regeneration, current medical applications are focused on the treatment of wounds and skin diseases. Since CAP is also able to inactivate cancer cells, its use in cancer therapy is expected to be the next field of clinical plasma application. Other promising applications are expected in oral medicine and ophthalmology. It is the current state of knowledge that biological CAP effects are mainly based on the action of reactive oxygen and nitrogen species supported by electrical fields and UV radiation. However, continuing basic research is not only essential to improve, optimize, and enlarge the spectrum of medical CAP applications and their safety, but it is also the basis for identification and definition of a single parameter or set of parameters to monitor and control plasma treatment and its effects. In the field of CAP plasma devices, research and application are currently dominated by two basic types: dielectric barrier discharges and plasma jets. Its individual adaptation to specific medical needs, including its combination with technical units for continuous and real-time monitoring of both plasma performance and the target that is treated, will lead to a new generation of CAP-based therapeutic systems. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma is the most aggressive type of skin cancer with a not-sufficient clinical outcome. High tumor mutation rates often hamper a remedial treatment, creating the need for palliative care in many patients. To reduce pain and burden, local palliation often includes cryo-ablation, immunotherapy via injection of IL2, or electrochemotherapy. Yet, a fraction of patients and lesions do not respond to those therapies. To reach even these resistances in a redox-mediated way, we treated skin biopsies from human melanoma ex vivo with cold physical plasma (kINPen MED plasma jet). This partially ionized gas generates a potent mixture of reactive oxygen species (ROS). Physical plasmas have been shown to be potent antitumor agents in preclinical melanoma and clinical head and neck cancer research. The innovation of this technology lies in its ease-of-use without anesthesia, as the "cold" plasma temperature of the kINPen MED does not exceed 37 °C. In metastatic melanoma skin biopsies from six patients, we identified a marked increase of apoptosis with plasma treatment ex vivo. This had an impact on the chemokine/cytokine profile of the cultured biopsies, e.g., three of six patient-derived biopsy supernatants showed an apparent decrease in VEGF compared to non-plasma treated specimens. Moreover, the baseline release levels of 24 chemokines/cytokines investigated may serve as a useful tool for future research on melanoma skin biopsy treatments. Our findings suggest a clinically useful role of cold physical plasma therapy in palliation of cutaneous melanoma lesions, possibly in a combinatory setting with other immune therapies. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) have been subject of increasing interest in the pathophysiology and therapy of cancers in recent years. In skin cancer, ROS are involved in UV-induced tumorigenesis and its targeted treatment via, e.g., photodynamic therapy. Another recent technology for topical ROS generation is cold physical plasma, a partially ionized gas expelling dozens of reactive species onto its treatment target. Gas plasma technology is accredited for its wound-healing abilities in Europe, and current clinical evidence suggests that it may have beneficial effects against actinic keratosis. Since the concept of hormesis dictates that low ROS levels perform signaling functions, while high ROS levels cause damage, we investigated herein the antitumor activity of gas plasma in non-melanoma skin cancer. In vitro, gas plasma exposure diminished the metabolic activity, preferentially in squamous cell carcinoma cell (SCC) lines compared to non-malignant HaCaT cells. In patient-derived basal cell carcinoma (BCC) and SCC samples treated with gas plasma ex vivo, increased apoptosis was found in both cancer types. Moreover, the immunomodulatory actions of gas plasma treatment were found affecting, e.g., the expression of CD86 and the number of regulatory T-cells. The supernatants of these ex vivo cultured tumors were quantitatively screened for cytokines, chemokines, and growth factors, identifying CCL5 and GM-CSF, molecules associated with skin cancer metastasis, to be markedly decreased. These findings suggest gas plasma treatment to be an interesting future technology for non-melanoma skin cancer topical therapy. [ABSTRACT FROM AUTHOR]

The first Therapeutic ROS and Immunity in Cancer (TRIC) meeting was organized by the excellence research center ZIK plasmatis (with its previous Frontiers in Redox Biochemistry and Medicine (FiRBaM) and Young Professionals' Workshop in Plasma Medicine (YPWPM) workshop series in Northern Germany) and the excellence research program ONKOTHER-H (Rostock/Greifswald, Germany). The meeting showcased cutting-edge research and liberated discussions on the application of therapeutic ROS and immunology in cancer treatment, primarily focusing on gas plasma technology. The 2-day hybrid meeting took place in Greifswald and online from 15–16 July 2021, facilitating a wide range of participants totaling 66 scientists from 12 countries and 5 continents. The meeting aimed at bringing together researchers from a variety of disciplines, including chemists, biochemists, biologists, engineers, immunologists, physicists, and physicians for interdisciplinary discussions on using therapeutic ROS and medical gas plasma technology in cancer therapy with the four main sessions: "Plasma, Cancer, Immunity", "Plasma combination therapies", "Plasma risk assessment and patients studies", and "Plasma mechanisms and treated liquids in cancer". This conference report outlines the abstracts of attending scientists submitted to this meeting. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (SCC) is the most prevalent cancer worldwide, increasing the cost of healthcare services and with a high rate of morbidity. Its etiology is linked to chronic ultraviolet (UV) exposure that leads to malignant transformation of keratinocytes. Invasive growth and metastasis are severe consequences of this process. Therapy-resistant and highly aggressive SCC is frequently fatal, exemplifying the need for novel treatment strategies. Cold physical plasma is a partially ionized gas, expelling therapeutic doses of reactive oxygen and nitrogen species that were investigated for their anticancer capacity against SCC in vitro and SCC-like lesions in vivo. Using the kINPen argon plasma jet, a selective growth-reducing action of plasma treatment was identified in two SCC cell lines in 2D and 3D cultures. In vivo, plasma treatment limited the progression of UVB-induced SSC-like skin lesions and dermal degeneration without compromising lesional or non-lesional skin. In lesional tissue, this was associated with a decrease in cell proliferation and the antioxidant transcription factor Nrf2 following plasma treatment, while catalase expression was increased. Analysis of skin adjacent to the lesions and determination of global antioxidant parameters confirmed the local but not systemic action of the plasma anticancer therapy in vivo. [ABSTRACT FROM AUTHOR]

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice. [ABSTRACT FROM AUTHOR]

Gas plasma is a partially ionized gas increasingly recognized for targeting cancer. Several hypotheses attempt to explain the link between plasma treatment and cytotoxicity in cancer cells, all focusing on cellular membranes that are the first to be exposed to plasma-generated reactive oxygen species (ROS). One proposes high levels of aquaporins, membrane transporters of water and hydrogen peroxide, to mark tumor cell line sensitivity to plasma treatment. A second focuses on membrane-expression of redox-related enzymes such as NADPH oxidases (NOX) that may modify or amplify the effects of plasma-derived ROS, fueling plasma-induced cancer cell death. Another hypothesis is that the decreased cholesterol content of tumor cell membranes sensitizes these to plasma-mediated oxidation and subsequently, cytotoxicity. Screening 33 surface molecules in 36 tumor cell lines in correlation to their sensitivity to plasma treatment, the expression of aquaporins or NOX members could not explain the sensitivity but were rather associated with treatment resistance. Correlation with transporter or enzyme activity was not tested. Analysis of cholesterol content confirmed the proposed positive correlation with treatment resistance. Strikingly, the strongest correlation was found for baseline metabolic activity (Spearman r = 0.76). Altogether, these data suggest tumor cell metabolism as a novel testable hypothesis to explain cancer cell resistance to gas plasma treatment for further elucidating this innovative field's chances and limitations in oncology. [Display omitted] • Using a 33 surface marker screening in 38 human cell lines, three major hypothesis were tested on gas plasma cancer treatment. • Expression of aquaporins and redox-related enzymes correlated with plasma treatment resistance in cancer cells. • Basal metabolic activity showed the best correlation to gas plasma treatment resistance in tumor cells. [ABSTRACT FROM AUTHOR]