Riboflavin photochemical therapy triggered PANoptosis by inducing mitochondrial damage in circulating colorectal cancer cells

Colorectal cancer (CRC) metastasis, driven by circulating tumor cells (CTCs), remains a formidable clinical challenge, positioning CTCseradication as a pivotal yet underexploited therapeutic frontier for metastasis prevention. Riboflavin photochemical therapy (RPT) has emerged as a promising modality due to its dual capacity to inactivate tumor cells while inducing minimal hematological toxicity. However, the optimal parameters and mechanisms behind RPTmediated CTCs inactivation are still unclear. Here, we present RPT as a novel strategy to eradicate CTCs while preserving blood cell integrity. Through systematic investigations, we pioneered the application of blue light for CTCs inactivation and established optimized RPT parameters that achieve complete CTCs' elimination with minimal impact on coagulation, immune cell functionality, and erythrocyte integrity. Mechanistically, RPT triggers mitochondrial dysfunction and oxidative stress, amplifying mitochondrial reactive oxygen species (mtROS) to induce PANoptosis, a coordinated cell death program integrating pyroptosis, apoptosis, necroptosis, and ferroptosis, in CRC cells. Transcriptomic profiling and pharmacological inhibition confirmed mtROS as the central mediator, with antioxidants rescuing PANoptotic markers and restoring cell viability. Unlike conventional therapies, RPT exploits riboflavins tumorselective mitochondrial accumulation, ensuring targeted cytotoxicity without compromising blood homeostasis. Overall, this study not only deciphers the mtROSPANoptosis axis as a therapeutic vulnerability but also establishes RPT as a promising intervention to disrupt metastatic dissemination in CRC.