Inverse Correlation between Endoplasmic Reticulum Stress Intensity and Antitumor Immune Response with Ruthenium(II)-Based Photosensitizers for the Photodynamic Therapy of Head and Neck Squamous Cell Carcinoma

Photodynamic therapy (PDT) is a promising strategy for
head and
neck squamous cell carcinoma (HNSCC), but the immune consequences
of tumor cell death remain incompletely understood. We compared two
ruthenium(II) polypyridine photosensitizers (PSs) in HNSCC models
and found that both were potently phototoxic (nanomolar IC50s), triggered diverse cell death pathways (including autophagy and
ferroptosis), and promoted hallmark danger signals of immunogenic
cell death (ICD). Strikingly, only one PS induced apoptosis and strong
endoplasmic reticulum (ER) stress, yet paradoxically led to immune
tolerance in vivo. Conversely, the PS that did not
induce apoptotic cell death with milder stress responses resulted
in a better antitumor immunity in vivo. These unexpected
findings challenge the prevailing view that PDT-triggered apoptosis
and ER stress are essential for ICD. Our study underscores the complexity
of PDT-induced cell death balance and immunogenic signals and highlights
the need to redefine ICD-inducing criteria for the rational design
of next-generation PSs.