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 IC<sub>50</sub>s), 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 <i>in vivo</i>. Conversely, the PS that did not induce apoptotic cell death with milder stress responses resulted in a better antitumor immunity <i>in vivo</i>. 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.
Authors
- Johannes Karges (ORCID: https://orcid.org/0000-0001-5258-0260)
- Christian Gaiddon (ORCID: https://orcid.org/0000-0003-4315-3851)
- Matthieu Scarpi‐Luttenauer (ORCID: https://orcid.org/0000-0001-8003-9527)
- Albert Gandioso (ORCID: https://orcid.org/0000-0002-5114-8502)
- Sébastien Harlepp (ORCID: https://orcid.org/0000-0001-8891-7953)
- Mickaël Burgy (ORCID: https://orcid.org/0000-0001-5724-3677)
- Gilles Gasser (ORCID: https://orcid.org/0000-0002-4244-5097)
- Alain C. Jung (ORCID: https://orcid.org/0000-0002-4049-4151)
- Chloé Thibaudeau
- Lei Zhou (ORCID: https://orcid.org/0000-0003-4709-3198)
- Georg Mellitzer (ORCID: https://orcid.org/0000-0003-4467-0789)
- Cyril Bour (ORCID: https://orcid.org/0000-0001-6296-7653)
- Alexandre Detappe (ORCID: https://orcid.org/0000-0001-9364-1621)
- Pierre Mesdom (ORCID: https://orcid.org/0000-0003-1069-2138)
- Sophie Martin (ORCID: https://orcid.org/0000-0002-2907-7445)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Chimie ParisTech - PSL (FR)
- Inserm (FR)
- Université Paris Sciences et Lettres (FR)
- Regenerative NanoMedicine (FR)
- Institut de Cancérologie Strasbourg (FR)
- Laboratoire de Biophotonique et Pharmacologie (FR)
- Metrogiprotrans (Russia) (RU)
- NOAA Chemical Sciences Laboratory (US)
- Biotechnologie et Signalisation Cellulaire (FR)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-19
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02147
- Citations
- 1
- Primary Topic
- Photodynamic Therapy Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.52