Weiqi Zhang a b 1, Linjia Chen a 1, Yahui Dong a 1, Yinghua Zeng b, Yongyu Chen a, Yue Liu a, Jingru Wang a, Fujun Shi a

DOI:10.1016/j.jconrel.2026.114829

https://doi.org/10.1016/j.jconrel.2026.114829

Abstract

       Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to the lack of druggable targets and intrinsic resistance to conventional therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a promising therapeutic vulnerability in TNBC. Here, we identify solute carrier family 7 member 5 (SLC7A5) as a ferroptosis-suppressing prognostic target, and develop a tumor microenvironment (TME)-responsive camptothecin (CPT)-peptide conjugates (CPCs) nanoassembly for in situ delivery of the SLC7A5 inhibitor JPH203 to TNBC. The CPCs integrate an active tumor targeting motif, a CPT-based hydrophobic core that drives self-assembly, and a gelatinase-cleavable linker for enzyme-responsive disassembly. Upon TME-triggered release, JPH203 effectively blocks leucine uptake, suppresses mTORC1 signaling, disrupts iron and redox homeostasis, and synergizes with mitochondrial reactive oxygen species to induce potent ferroptosis, achieving an 81.2% tumor growth suppression rate in orthotopic 4 T1 models with favorable biosafety. Importantly, CPCs-JPH promotes dendritic cell maturation, activates CD8+ T-cell responses, and significantly improves survival outcomes in orthotopic 4 T1 tumor-bearing mice. This work establishes a multifunctional and enzyme-responsive nanoplatform that harnesses ferroptosis to overcome therapeutic resistance while concurrently engaging innate and adaptive immunity in TNBC.

Graphical abstract