Regulated cell death mechanisms in mitochondria-targeted phototherapy

Phototherapy, comprising photodynamic therapy (PDT) and photothermal therapy (PTT), was first introduced over a century ago and has since evolved into a versatile cancer treatment modality. While numerous studies have explored regulated cell death (RCD) mechanisms induced by phototherapy, a comprehensive synthesis centered on mitochondria-targeted phototherapeutic strategies and agents as mediators of RCD is still lacking. This review provides a systematic and in-depth analysis of recent advances in mitochondria-centered mechanisms driving phototherapy-induced death pathways, including apoptosis, autophagy, pyroptosis, immunogenic cell death, ferroptosis, and cuproptosis. We highlight the critical role of mitochondria as central regulators of these death pathways in response to phototherapeutic interventions. Moreover, we discuss fundamental design strategies for developing precision-targeted phototherapeutic materials to enhance efficacy and minimize off-target effects. Finally, we identify prevailing challenges and propose future research directions to address these hurdles, paving the way for next-generation mitochondria-targeted phototherapy as a highly effective strategy for cancer management.