Nano co-inducer of immunogenic cell death and ferroptosis for anti-tumor immunotherapy

Abstract

Due to population aging and lifestyle changes, the global tumor burden has increased, making tumor disease a significant challenge in public health. Recently, immunotherapy emerged as an effective approach for tumor treatment by activating and enhancing the body’s immune system to precisely identify and attack tumor cells. However, its efficacy was limited by the “cold” immunosuppressive tumor microenvironment (ITME) and the tissue repair capabilities of tumors. To address this issue, we developed a dual-target ferroptosis immune-inducer, FTB@CC, which releases photosensitizer (PS), calcium (Ca²⁺), and Fe²⁺ under weakly acidic conditions. Upon near-infrared (NIR) laser irradiation, PSs induced endoplasmic reticulum (ER) stress, producing large amounts of reactive oxygen species (ROS) and releasing significant quantities of damage-associated molecular patterns (DAMPs), which mediated immunogenic cell death (ICD). Simultaneously, Ca²⁺ overload activates the inflammasome and amplifies cellular cytotoxicity for DAMPs release, eventually activating the ICD pathway. The supplementation of Fe²⁺ increased iron storage within tumor cells and downregulated the expression of glutathione peroxidase 4 (GPX4), leading to the accumulation of lipid peroxides (LPO) and ultimately resulting in ferroptosis. This multi-level interaction strategy restructured the ITME and induced ICD, overcoming the limitations of single-agent therapies, and significantly enhancing the efficacy of anti-PD-L1 antibody (α-PD-L1) in suppressing tumor cell immune evasion. As a result, it promoted the infiltration of immune cells and inhibited both distal and proximal tumors. This nano-integrated ICD-ferroptosis co-inducer offers an intelligent strategy for effectively overcoming ITME, thereby providing a promising avenue for advanced immunotherapeutic interventions.