Modulation of cellular signaling and innate immune mechanisms by cold atmospheric plasma.

Cold atmospheric plasma (CAP) has emerged as a tunable physicochemical stimulus capable of modulating immune responses through the controlled delivery of reactive oxygen and nitrogen species (RONS), charged particles, transient electric fields, and photons at near-ambient temperature. While the antimicrobial and cytotoxic applications of CAP are well established, evidence regarding its role as a regulator of innate immune signaling remains fragmented across the literature. Inconsistent dosimetry reporting is a noted issue, and a unified framework linking plasma-generated redox signals to specific immune cell outcomes is lacking. This narrative review focuses on the effects of CAP on innate immune mechanisms and the cellular signaling pathways that translate plasma-derived redox cues into biological responses. We first outline how device architecture, gas composition, treatment mode, and dose shape the qualitative and quantitative RONS profile that reaches biological targets. We then discuss key redox-sensitive signaling pathways, including NF-κB, Nrf2-Keap1, MAPK, PI3K-AKT-mTOR, HIF-1α, mitochondrial pathways, and inflammasome activation. While NF-κB, Nrf2-Keap1, and MAPK signaling are supported across multiple independent studies, evidence for HIF-1α and specific inflammasome subtypes is limited and derived from a smaller number of experimental models. Particular emphasis is placed on macrophage polarization, where available evidence indicates that CAP may promote either proinflammatory, antimicrobial M1-like programs or anti-inflammatory, tissue-repairing M2-like phenotypes depending on exposure parameters and tissue context. We further summarize more limited and still-emerging evidence that CAP influences dendritic cell maturation, antigen-presenting capacity, neutrophil migration and neutrophil extracellular trap (NET) formation, and natural killer (NK) cell-mediated tumor-cell recognition. Collectively, current evidence indicates that CAP is not merely a cytotoxic or antimicrobial modality but a potential dose- and context-dependent regulator of innate immune function, though findings vary across plasma sources and experimental models. A deeper understanding of CAP dosimetry, RONS chemistry, and cell-type-specific redox thresholds will be essential for facilitating future clinical translation into applications in infection control, wound healing, inflammation, and oncology.