Modulation of MOF Catalytic Activity to Exploit Cystine Dependency for Immunometabolic Therapy

Abstract Tumor immunometabolism plays an important role in tumor progression and immune cell activity and is therefore critical to the efficacy of cancer immunotherapy. Modulation of immunometabolism to boost cancer immunotherapy is mostly based on targeting tumor cell metabolism, which often fails to address the tumor-promoting functions maintained by stromal cells. In contrast, targeting a metabolic checkpoint shared by tumor cells and cancer-associated fibroblasts (CAFs) can potentially overcome this limitation but has been relatively underexplored. Herein, a locally delivered, ultrasound activatable nanocatalytic platform is reported for immunometabolic cancer therapy. The platform is composed of sulfasalazine and a gallium-modified Fe-TCPP metal–organic framework nanozyme codelivered in an oxidized sodium alginate-based hydrogel. Ultrasound-activated gallium-modified Fe-TCPP boosts electron transfer, peroxide activation, and reactive oxygen species production while disrupting iron balance. Simultaneously, sulfasalazine inhibits SLC7A11-mediated cystine uptake in CAFs and tumor cells, reducing matrix remodeling and weakening the tumor’s antioxidant defense. This dual approach increases oxidative stress, reshapes the tumor microenvironment, induces immunogenic tumor cell death with ferroptotic traits, matures dendritic cells, and strengthens CD8+ T-cell responses. Consequently, it suppresses tumor growth in an immunocompetent osteosarcoma model and remains effective in a patient-derived OSCC xenograft model. Together, these findings demonstrate that targeting shared SLC7A11-mediated cystine dependence integrates stromal remodeling, tumor redox disruption, and antitumor immune activation.