The Inorganic Chemical Biology (ICB) team led by Professor Gilles Gasser, within the Institute of Chemistry for Life and Health Sciences (i-CLeHS), develops innovative approaches in chemical biology for health. The team has designed a photoactive agent capable of inducing pyroptosis in a controlled manner, a form of programmed cell death at the heart of emerging anticancer immunotherapy strategies.

Understanding and controlling pyroptosis. At the Institute of Chemistry for Life and Health Sciences, researchers from Gilles Gasser’s group have achieved a major step forward in the development of new therapeutic approaches against cancer. Their work focuses on pyroptosis, an inflammatory form of cell death now considered particularly promising for stimulating antitumor immune responses. Until now, compounds capable of triggering this process were most often identified serendipitously, limiting their optimization and mechanistic understanding.

An innovative conjugate with remarkable properties. To address this challenge, the team designed a novel conjugate, named Os-IMD, by covalently linking an osmium(II)-based photosensitizer to a glutamine transport inhibitor. This compound displays remarkable properties: strong absorption in the deep red region, high photostability, excellent distribution in protein-containing systems, and strong phototoxicity in both 2D cell cultures and 3D spheroid models. Thanks to selective uptake via the ASCT2 transporter and mitochondrial localization, Os-IMD acts in a highly specific manner compared to the unconjugated osmium complex.

A major breakthrough for photodynamic therapy. Upon light irradiation, this photosensitizer reprograms cellular metabolism, disrupts redox homeostasis and mitochondrial respiration, ultimately triggering the Caspase-1/GSDMD pathway and inducing controlled pyroptosis. These results open the way to a new generation of therapeutic agents in photodynamic therapy, based on well-defined mechanisms of action. Published in the Journal of the American Chemical Society, this work highlights the excellence and innovation capacity of Chimie ParisTech–PSL teams in the field of chemistry for health.

Questions to Professor Gilles Gasser:

Gilles, how could this discovery concretely change the way certain cancers are treated?

The goal of this research is to develop new molecules that kill cancer cells through a combination of mechanisms, including the induction of immune memory. It is a way of teaching the body to fight against a potential resurgence of cancer cells (relapse and metastasis)—the body learns to fight on its own without the need for further chemotherapeutic treatment.. This immune response, generated by the combination of the compound developed in this study and light, is definitely very promising.

Why is it important today to develop light-activated therapies such as the one you are proposing?

Patients undergoing conventional chemotherapy face very significant side effects that go far beyond hair loss. That is why there is a high demand for the development of highly targeted treatments that use light to target only tumor cells or a specific area.

This breakthrough concretely illustrates the ability of therapeutic chemistry to turn fundamental concepts into innovative treatment strategies, paving the way for more targeted and more effective approaches against cancer.

Further reading.