Mitochondria-targeted ROS burst synergistically induces pyroptosis and remodels the immune microenvironment to enhance photodynamic efficacy against colorectal cancer

Abstract Over the past decades, the prognosis for patients with advanced colorectal cancer (CRC) remains unsatisfactory, indicating persistent challenges in current treatment modalities. Photodynamic therapy (PDT) has emerged as a promising local treatment option for CRC. However, the efficacy of PDT is severely constrained by tumor hypoxia and an over-reliance on apoptotic pathways, which fail to induce robust immunogenic cell death (ICD). Pyroptosis, a pro-inflammatory form of regulated cell death (RCD) characterized by the release of abundant damage-associated molecular patterns (DAMPs), holds the potential to enhance the ICD effect of PDT and thereby improve its anti-tumor immune efficacy. Notably, emerging evidence suggests that mitochondrial dysfunction may play a key role in enhancing reactive oxygen species (ROS) generation and triggering pyroptosis. In this study, we combined a mitochondria-targeting strategy with PDT to induce a burst of ROS and effectively trigger pyroptosis. Furthermore, we preliminarily identified the potential involvement of the NFκB signaling cascade in pyroptosis initiation. In conclusion, these findings provide new theoretical evidence for the role of mitochondria in orchestrating pyroptosis and offer a novel paradigm for precision photo-immunotherapy in CRC.