# Stimuli‐Responsive CuFeTe2 Nanosheets for Amplified Cuproptosis/Ferroptosis in Triple‐Negative Breast Cancer Therapy

## TL;DR

A new nanosheet material is developed to enhance cancer treatment by triggering two cell death pathways in breast cancer cells.

## Contribution

CuFeTe2 nanosheets synergistically amplify cuproptosis and ferroptosis in triple-negative breast cancer.

## Key findings

- CuFeTe2 nanosheets release Fe²⁺ and Cu²⁺ in acidic tumor environments to trigger ferroptosis and cuproptosis.
- NIR-II photothermal effects enhance oxidative stress and immune response in tumor cells.
- The nanosheets are biodegradable and safely excreted via the kidneys.

## Abstract

Triple‐negative breast cancer (TNBC) exhibits high copper and iron uptake, making cuproptosis and ferroptosis promising therapeutic strategies. However, their efficacy is limited by TNBC's intrinsic antioxidant defences. Herein, CuFeTe2 nanosheets (CFT) with internal tumour microenvironment (TME) responsiveness and external NIR‐II mild photothermal enhancement is developed to synergistically overcome this antioxidant defences, amplifying both pathways for improved TNBC therapy. In the acidic TME, CFT releases Fe2+ and Cu2+. Cu2+ reacted with glutathione (GSH) to generate Cu+, inhibiting glutathione peroxidase 4 (GPX4), amplifying lipid peroxidation (LPO), and triggering ferroptosis. Cu⁺ also induce dihydrolipoamide S‐acetyltransferase (DLAT) aggregation and disrupts iron‐sulfur (Fe–S) cluster proteins, initiating cuproptosis. Meanwhile, Fe2+ overload further reinforced ferroptosis. Both Fe2+ and Cu+ catalyze H2O2 decomposition into hydroxyl radicals (•OH), while NIR‐II photothermal effects accelerated this process, intensifying oxidative stress and ferroptosis. Moreover, ferroptosis depleted heat shock protein 70 (HSP70) and reduces ATP levels, sensitizing tumor cells to cuproptosis. The synergistic activation of ferroptosis and cuproptosis ultimately induced immunogenic cell death (ICD) and a potent immune response. Biodegraded CFT is efficiently excreted via renal filtration, ensuring high biocompatibility and safe clearance. This study presents a TME‐responsive, photothermal‐enhanced nanoplatform that effectively integrates ferroptosis and cuproptosis for potent antitumor therapy.

Dual‐stimuli‐responsive CuFeTe2 nanosheets (CFT) induce cuproptosis/ferroptosis via TME‐responsive Fe2⁺/Cu2⁺ release and NIR‐II photothermal effects, amplifying ROS and depleting HSP70/ATP to trigger ICD and immune activation, while ensuring biocompatible renal clearance for TNBC therapy.