Combining chemotherapy and cold atmospheric plasma treatment: Empirical and theoretical insights

Chemotherapy remains a cornerstone in oncology, but drug resistance and dose-dependent side effects limit its efficacy. Cold atmospheric plasma emerges as a powerful tool that can sensitize cancer cells and synergize with chemotherapy. It is an ionized gas and an exogenous source of reactive oxygen and nitrogen species that, similar to many chemotherapeutics, induces oxidative stress in cancer but in a more selective manner and is applied locally. Different plasma modalities (direct treatment and plasma-treated hydrogels and liquids) open a range of possibilities for use in a broad variety of cancers. In the first part, this review synthesizes the state of the art on plasma-chemotherapy combinations, discussing promising molecular targets and detailing mechanistic variations, alongside expected and observed effects for different chemotherapeutic classes. The second part discusses the variability in applied protocols and tumor models, stressing the need for standardized and informed study design in collaboration with clinicians to allow cross-study comparison and translatability.