Cold atmospheric plasma and adaptive antitumor immunity: current evidence with emphasis on T-cell responses

Cold atmospheric plasma (CAP) is a redox-based technology that generates reactive oxygen and nitrogen species (RONS) and is being investigated as a potential immunomodulatory approach for cancer therapy and other clinical indications. This narrative review evaluates current evidence concerning CAP-mediated regulation of adaptive antitumor immunity, with particular emphasis on T-cell responses, immunogenic cell death (ICD), antigen-presenting cell (APC) activation, tumor microenvironment (TME) remodeling, and combination treatment with immune checkpoint blockade. Available studies indicate that CAP influences T-cell immunity predominantly indirectly by inducing tumor cell stress and death, the release of damage-associated molecular patterns (DAMPs), increasing antigen availability, dendritic cell (DC) activation, and remodeling of cytokine and chemokine networks. Some studies also report direct effects of carefully dosed CAP exposure on primary T cells; however, these findings remain limited and must be balanced against the substantial oxidative sensitivity of resting lymphocytes. Calreticulin exposure, endoplasmic reticulum stress, mitochondrial oxidative responses, extracellular ATP, and HMGB1 release have been reported in CAP-treated tumor models and are compatible with ICD, but these markers alone do not establish functional antitumor immunogenicity. Stronger evidence for functionally relevant adaptive antitumor immunity includes functional antigen uptake and presentation by DC, tumor-specific T-cell responses, evidence of adaptive immune-cell dependence, prophylactic vaccination protection, and resistance to tumor rechallenge. Preclinical studies further suggest that CAP or plasma-activated liquids can increase intratumoral CD4 + and CD8 + T-cell infiltration and improve responses to immune checkpoint blockade. Evidence concerning B-cell and antibody responses remains sparse. Clinical studies have primarily addressed the feasibility, safety, antimicrobial activity, or wound-healing effects of superficial cold plasma applications and should not be interpreted as clinical validation of CAP-based cancer immunotherapy. Translation will require standardized device parameters, gas composition, exposure dose, RONS dosimetry, delivery formats, and immune monitoring. Overall, CAP is a promising but incompletely validated platform for converting localized redox effects into therapeutically useful adaptive immune responses.