O-GlcNAcylation in cellular senescence: From molecular insights to anti-cancer therapeutic opportunities

Cellular senescence is a dynamic stress response with broad implications in aging, tissue homeostasis, and disease. In anti-cancer therapies, senescence acts as a double-edged sword, initially suppressing tumor growth but contributing to therapy tolerance and minimal residual disease, later leading to tumor repopulation, and relapse. While senescent cells are the seat of a large-scale metabolic reprogramming, the specific contribution of O-GlcNAcylation, a nutrient-sensitive post-translational modification involved in cancer progression and therapy resistance, was only recently investigated. Here, we first summarize studies reporting changes in O-GlcNAcylation levels during senescence and how modulation of O-GlcNAc cycling enzymes influences senescence onset, maintenance, and escape. We then discuss evidence suggesting that O-GlcNAcylation may influence several hallmarks of senescence, including cell cycle arrest, DNA damage response, apoptosis resistance, metabolic rewiring and mitochondrial stress signaling. Finally, we discuss the potential therapeutic relevance of targeting O-GlcNAc cycling enzymes to modulate cancer cell senescence, limit senescence escape, and thereby improve anti-cancer treatment responses.