A glucose deprivation strategy to modulate the SLC7A11/GSH/GPX4 axis for synchronous induction of ferroptosis/disulfidptosis-like cell death and tumor microenvironment remodeling

Disulfidptosis and ferroptosis are emerging regulated cell death modalities for cancer therapy, both critically reliant on intracellular cystine/cysteine conversion along SLC7A11/glutathione/glutathione peroxidase 4 (SLC7A11/GSH/GPX4) antioxidant axis. However, their synchronous activation is hindered by the opposing roles of cystine transport. Leveraging their metabolic crosstalk, disrupting glucose homeostasis to induce nicotinamide adenine dinucleotide phosphate (NADPH) deficiency offers a rational strategy to overcome this limitation. Herein, we engineered a nanoinducer (VEP@HA-NO) by coordinating epigallocatechin gallate (EGCG) with vanadium for paclitaxel loading, followed by coating with a hyaluronic acid (HA)-NO conjugate to regulate SLC7A11/GSH/GPX4 axis. In this system, EGCG functions as glucose transport 1 (GLUT1) inhibitor, blocking glucose influx, limiting NADPH supply and suppressing cystine/cysteine conversion. This metabolic intervention yields two convergent effects: cystine accumulation provokes disulfide stress, while cysteine deficiency impairs GSH biosynthesis and deactivates GPX4, synchronously inducing disulfidptosis-like cell death and amplifying ferroptosis, thereby resolving the contradictory roles of cystine transport. Concurrently, vanadium delivery consumes GSH and generates hydroxyl radicals, further potentiating ferroptosis. Moreover, VEP@HA-NO inhibits cancer stem cells stemness and M2 macrophages polarization while enhancing T cells activity. Collectively, this work establishes a novel paradigm for simultaneously triggering ferroptosis/disulfidptosis-like cell death by disrupting glucose homeostasis, offering a promising strategy for enhanced antitumor therapy. Schematic illustration of the multifaceted therapeutic mechanisms mediated by VEP@HA-NO.