Dual-pathway nanoengineering: spatiotemporal control of immunogenic apoptosis and macrophage phenotype reprogramming for augmented antitumor immunity.

Damage-associated molecular patterns (DAMPs) are released by cells through immunogenic cell death (ICD), reshaping the tumor microenvironment and demonstrating significant potential in cancer immunotherapy. We report a type of nanoparticle (FeS-IMQ-MnO2@HA) in which Hyaluronic acid (HA) targets the CD44 receptor of tumor cells. Under low-temperature photothermal therapy (LTPTT), FeS within the nanoparticles generates Fe²⁺ through chemodynamic therapy (CDT), thereby producing reactive oxygen species (ROS) that mediate ICD and activate immune responses, enhancing the treatment of solid tumors. MnO₂ nanoparticles are used to lower glutathione (GSH) levels at tumor sites, increasing the anti-tumor activity of ROS. Concurrently, hydrogen sulfide (H₂S) modulates the metabolic environment of tumor cells, inducing acidosis and enhancing lactate production, which increases Ca²⁺ influx, leading to mitochondrial damage and the release of oxidized mitochondrial DNA. This promotes the transformation of tumor-associated macrophages to the M1 phenotype, enhancing the effectiveness of tumor immunotherapy. This strategy provides a new perspective by modulating the tumor microenvironment and activating immune responses, showcasing the potential of ICD in improving tumor treatment responses.