Cold Atmospheric Plasma for Breast Cancer Therapy: Mechanisms, Preclinical Evidence, and Translational Challenges

ABSTRACT The burden of breast cancer remains high as it is the most prevalent malignancy among women, with therapeutic success often limited by drug resistance, treatment toxicity, and tumor heterogeneity. Cold atmospheric plasma (CAP), a partially ionized gas enriched with reactive oxygen and nitrogen species (RONS), and electromagnetic waves, has emerged as a promising preclinical anticancer strategy with selctively killing. Here, we review the mechanisms of CAP action against breast cancer, including RONS‐mediated oxidative stress, mitochondrial disruption, apoptosis, immunogenic cell death, and suppression of metastatic and angiogenic pathways. Notably, preclinical studies indicate that CAP can target therapy‐resistant breast cancer stem‐like cells and may sensitize aggressive subtypes, particularly triple‐negative breast cancer (TNBC). Synergistic combinations with drug therapy, radiotherapy, immunotherapy, and surgery further support its therapeutic potential as an adjunctive strategy in preclinical breast cancer research. Advances in delivery platforms, such as plasma‐activated media and hydrogels, may help address CAP's instability and improve local delivery. Despite promising preclinical results, clinical translation faces barriers such as the short half‐life of RONS, device standardization, and unresolved immunomodulatory effects. Further standardized in vivo studies and breast‐cancer‐specific clinical trials are required before CAP can be considered clinically ready for breast cancer therapy.