An activatable antibody conjugate for cold tumors: Synergistic ferroptosis and immunotherapy via photodynamic PD-L1 targeting

Immunotherapy targeting PD-L1 has shown limited efficacy in immunologically "cold" tumors, primarily due to the inability to initiate a robust antitumor immune response. To address this, we developed a chemically engineered, activatable PD-L1 antibody conjugate designed to remodel the tumor microenvironment and potentiate systemic immunity. This multifunctional agent integrates a glutathione (GSH)-responsive element and a Photosensitizer, enabling targeted delivery and localized activation upon binding PD-L1 on tumor cells. Upon light irradiation, the conjugate depletes GSH and generates substantial Reactive Oxygen Species (ROS), synergistically amplifying oxidative stress and inducing Ferroptosis. This process is accompanied by calreticulin exposure, enhanced antigen presentation, and subsequent T-cell activation. Furthermore, the platform allows real-time visualization of treatment response, offering a theranostic strategy for cold tumors. This work provides a powerful and scalable approach to overcome resistance to conventional immune checkpoint therapy.

Cold tumor; PDL1 therapy; Photodynamic therapy.