AACR 2026: Targeting replication stress promotes immunogenic cell death in chordoma

Our research team previously identified replication stress as a key therapeutic vulnerability in chordoma. Replication stress occurs when a cell has difficulty copying its DNA, and our work shows this phenomenon is especially pronounced in chordoma. Drugs such as gemcitabine and ATR inhibitors exacerbate replication stress, leading to severe DNA damage and cell death. New data now show that this process may also stimulate antitumor immunity as treatment with replication stress targeting drugs led to accumulation of extranuclear DNA, activation of type I interferon signaling, release of immunomodulatory factors, and increased expression of MHC class I and PD-L1. These findings suggest that targeting replication stress could both directly damage chordoma cells and make them more visible to the immune system, supporting future strategies that combine these agents with immunotherapy.