A Glutamine-Metabolism-Intervening Nanoplatform Activates Lipophagy to Potentiate Ferroptosis and Immune Activation in Breast Cancer.

Aberrant glutamine (Gln) metabolism in tumor cells contributes to ferroptosis resistance and immunosuppression, challenging ferroptotic therapy. Our preliminary bioinformatic data uncovered that elevated expression of SLC1A5, a critical Gln transporter, confers poor prognosis in breast cancer, underscoring its potential as a therapeutic target for metabolic regulation. Encouraged by this, this work proposes to enhance ferroptosis of breast cancer by inhibiting SLC1A5. As a proof-of-concept, we develop a nanoplatform for ferroptosis named MICLM, which is obtained by encapsulating chlorin e6 (Ce6, a photosensitizer) and IMD-0354 (an SLC1A5 inhibitor) into metal-organic framework (NH-MIL-101(Fe)), followed by surface coating for tumor-targeting. Experimental data reveal that Ce6-based photodynamic therapy synergizes with iron-mediated Fenton reaction, potently driving lipid peroxides (LPOs) accumulation and triggering ferroptosis of 4T1 cells. Meanwhile, IMD-0354-mediated Gln metabolic intervention is proven to inhibit glutathione (GSH) synthesis and activate lipophagy, thereby increasing free fatty acids (FFA) levels as an essential "fuel" for lipid peroxidation and overcoming a key limitation in ferroptosis efficacy. Additionally, Gln metabolism inhibition attenuates immunosuppressive M2 macrophage polarization, ultimately boosting antitumor immunity. Thus, MICLM effectively induces ferroptosis and remodels the tumor immune microenvironment via amino acid metabolic intervention, offering a promising strategy for ferroptosis-based therapy.