Immunogenic Cell Death in Melanoma Induced by Radiotherapy, Photodynamic Therapy, or Non-Thermal Plasma: The Role of Reactive Oxygen and Nitrogen Species

Abstract

Melanoma is characterised by profound immune evasion, and although immune checkpoint inhibitors (ICIs) have transformed clinical management, durable responses remain limited to a subset of patients. Therapies that induce immunogenic cell death (ICD) can enhance anti-tumour immunity by converting dying tumour cells into a source of tumour antigens and danger signals. Radiotherapy (RT), photodynamic therapy (PDT), and non-thermal plasma (NTP) are three pro-oxidant cancer therapies that induce ICD through the generation of reactive oxygen and nitrogen species (RONS), yet these modalities are rarely compared from the perspective of the characteristics of the RONS they produce. This review compares these modalities through a mechanistic framework in which RONS composition, site of generation, lifetime, and diffusion shape the intracellular compartments exposed to oxidative stress and the resulting immune-relevant responses. These characteristics influence which intracellular compartments sustain oxidative damage, thereby shaping endoplasmic reticulum (ER) stress, DNA-damage sensing, and mitochondrial dysfunction. The resulting stress responses can promote damage-associated molecular pattern emission and create conditions that support anti-tumour immune activation. Across the available literature, RT is commonly associated with cytosolic DNA sensing and type I interferon signalling, PDT frequently involves photosensitiser-localisation-dependent ER stress and calreticulin exposure, and NTP can engage several stress pathways in a treatment-parameter-dependent manner. These patterns are overlapping rather than exclusive and depend on the experimental variables of each treatment modality and the tumour biological context. By integrating these mechanistic differences, this review aims to provide a framework for understanding how RONS characteristics shape ICD and its associated anti-tumour immune effects, and how these pro-oxidant therapies may be combined with ICIs in melanoma. Because direct head-to-head comparisons using matched melanoma models and common immunological endpoints remain limited, the proposed modality-associated patterns should be interpreted as context-dependent tendencies rather than a fixed mechanistic hierarchy.