Disulfidptosis Nanoinducer Interrupts Tumor Metabolic Privilege to Boost Sustained Immunotherapy
Yan Xu, Xiaoqi Ming, Jin Qi, Zhenqiu Huang, Hongling Zhu, Mingyu Wu, Shun Feng, Yu Wan
Abstract
Malignant tumor metabolic reprogramming drives proliferation and immune evasion by hijacking essential nutrients and shaping an immunosuppressive microenvironment. Although targeting tumor metabolism offers therapeutic promise, selectively modulating aberrant metabolic pathways without affecting normal cells remains a major challenge. Disulfidptosis, a recently identified form of metabolism-dependent regulated cell death, may offer an avenue for metabolic disruption; however, its immunomodulatory potential remains unexplored. Here, a disulfidptosis nanoinducer (CYBC NPs), which was constructed with cancer cell membrane-camouflaged nanoplatform coloaded with cystine and the GLUT1 inhibitor BAY-876, was designed to selectively induce disulfidptosis in triple-negative breast cancer cells. By concurrently blocking glucose uptake and supplementing cystine, CYBC NPs triggered disulfidptosis-mediated cytoskeletal collapse, relocated tumor metabolic fluxes, and induced immunogenic cell death. This metabolic perturbation promoted dendritic cell maturation, M1-like macrophage polarization, and cytotoxic T lymphocyte activation, thereby reversing ITME and suppressing tumor growth. Notably, CYBC NPs elicited robust, nonexhausted antitumor immunity and generated durable immune memory, effectively preventing tumor recurrence and metastasis. Together, our study demonstrated the implementation of disulfidptosis as a standalone immunotherapeutic strategy, offering a paradigm shift in metabolism-driven cancer immunotherapy.