Combining cell death & immunity The perfect act

Cellular senescence is a stable stress response induced by diverse physiological insults and clinically relevant cancer therapies, including chemotherapy. While senescence contributes to tumor suppression by preventing the proliferation of damaged cells, the persistence of senescent cells promotes tissue dysfunction, chronic inflammation, and therapy-associated toxicities. Despite the availability of numerous senescence-inducing agents, the identification of selective senolytic strategies remains a major challenge, in part because senescent cells are non-proliferative and poorly suited to conventional genetic screening approaches.
In this thesis, we developed an inducible CRISPR-Cas9 screening platform to systematically identify genetic vulnerabilities of non-proliferative cellular states. Applying this approach to therapy-induced senescence uncovered the mitochondrial transporter SLC25A23 as a selective senolytic target. Pharmacological inhibition using salinomycin phenocopied SLC25A23 loss and, in combination with a Death Receptor 5 (DR5) agonistic antibody, synergistically eliminated senescent cells while promoting immunogenic cell death. Extending these findings in vivo, we demonstrate that chemotherapy-induced senescence contributes directly to multiple adverse effects of doxorubicin, including systemic inflammation, cardiac dysfunction, impaired physical performance, and bone marrow suppression. Pharmacological clearance of senescent cells effectively alleviated these toxicities, providing therapeutic validation of senescence as a driver of chemotherapy-associated side effects.
Finally, this thesis examines how molecules released during regulated cell death shape anti-tumor immunity. We propose that the immunological consequences of cell death are governed not only by the balance between immunogenic and pro-resolving signals, but also by their temporal dynamics, whereby identical mediators can promote either anti- or pro-tumorigenic responses depending on the timing of their release.