Injectable anti-inflammatory nanofiber hydrogel reprograms immunosuppressive tumor microenvironment via cascade-amplified immunogenic cell death

Immunogenic cell death (ICD) attracts significant attention by initiating adaptive immune responses for antitumor immunotherapy. Although ROS is developed to trigger ICD as an inducer, the effect of immunotherapy is compromised by the scavenging of ROS in the immunosuppressive tumor microenvironment. Herein, we report an injectable cascade-amplified ICD nanofiber hydrogel self-assembled from steroid drug prednisolone sodium phosphate (PSP) and calcium chloride for the local delivery of glutaminase inhibitor CB-839 and the sonosensitizer Ce6 (CCPG). ROS is generated by stimulating Ce6 under ultrasound (US), which disrupts the Ca 2+ buffer capacity of mitochondria to induce Ca 2+ influx, thereby triggering ICD to release damage-associated molecular patterns (DAMPs) from dying tumor cells for initiating T cell infiltration. Moreover, ICD induction is further amplified by the glutaminase inhibitor CB-839. CB-839 suppresses glutathione (GSH) synthesis by inhibiting the conversion of glutamine to glutamate as the precursor of GSH, thereby limiting the scavenging of Ce6-generated ROS and enhancing their antitumor and ICD-triggering effects. Additionally, anti-inflammatory PSP suppresses matrix metalloproteinase-2 (MMP-2) expression, resulting in facilitating T cell infiltration. As a consequence, this work highlights a strategy to reprogram immunosuppressive tumor microenvironment via cascade-amplified ICD by inhibiting the scavenging of ROS to maintain Ca 2+ overload, providing new insights for enhancing the efficacy of immunotherapy.