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A peptide-based nano-PROTAC synergistically driving ferroptosis-immunotherapy in triple-negative breast cancer
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DOI：10.1016/j.apsb.2026.07.045.png)
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Abstract
En 中文
Ferroptosis, an emerging mechanism of cell death, provides new targets for the treatment of triple-negative breast cancer (TNBC). Glutathione peroxidase 4 (GPX4), a key regulator of ferroptosis, is a promising therapeutic target for TNBC. Given that GPX4 is often considered “undruggable”, proteolysis targeting chimeras (PROTACs) offer a powerful means for its degradation. However, conventional PROTACs often face challenges in achieving precise localization and potent activation in vivo. Herein, we engineered a peptide-based nano-PROTAC, named CMVG, which couples VHL- and GPX4-binding peptides with iron-based metal–organic frameworks via a “click” reaction and loads the photosensitizer chlorin e6 (Ce6). CMVG enhances ferroptosis through a dual mechanism: it degrades GPX4 via its PROTAC function to initiate ferroptosis, while generating reactive oxygen species under laser irradiation to mediate photodynamic therapy, thereby intensifying oxidative stress and accelerating ferroptosis. Furthermore, the ferroptosis induced by CMVG is highly immunogenic, triggering immunogenic cell death and reshaping the tumor immune microenvironment, ultimately boosting the anti-TNBC immune response. Additionally, CMVG exhibits excellent targeting and biocompatibility, enabling MRI-guided tumor treatment. This work presents the first peptide-based nano-PROTAC for GPX4 degradation, overcoming major limitations of conventional PROTACs, and offers a promising integrated strategy for treating TNBC.
Keywords:
Nano-PROTAC
Peptide
GPX4
Ferroptosis
Immunogenic cell death
Immunotherapy
Photodynamic therapy
Triple-negative breast cancer
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