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A ferroptosis-priming gene therapy for post-surgical cancer recurrence
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DOI：10.1016/j.apsb.2026.08.002.png)
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Abstract
En 中文
Ferroptosis provides a promising strategy to overcome postoperative relapse by eliminating tumor cells resistant to conventional therapies. However, the clinical translation of ferroptosis inducers is limited by their narrow therapeutic window and non-immunogenic nature. In this study, we demonstrate that adeno-associated virus (AAV)-mediated p53 reactivation effectively addresses these limitations: it not only sensitizes tumor cells to ferroptosis by transcriptionally repressing the cystine transporter SLC7A11 and upregulating the lipoxygenase ALOX12, but also reverses the non-immunogenic character of ferroptosis by enhancing dendritic cell maturation and T cell activation. Based on these findings, we propose a ferroptosis-priming gene therapy that combines AAV-p53 with ferroptosis induction. To optimize localized treatment, we co-encapsulated AAV-p53 and nanoparticle-encapsulated ferroptosis inducers within a hydrogel, creating a postsurgical site-applicable system. This system significantly enhances drug retention at the tumor site while reducing anti-AAV neutralizing antibody responses. In postoperative mouse models, this therapy achieved complete tumor eradication in 70% of melanoma and 60% of bladder cancer cases, respectively. Importantly, the cured mice demonstrated robust long-term antitumor immunity, successfully rejecting tumor rechallenge. Our work establishes a new paradigm for postoperative cancer therapy by the ferroptosis-priming gene therapy, highlighting its promising clinical potential.
Keywords:
Ferroptosis
p53
gene therapy
Hydrogel delivery
Adeno-associated virus
Postoperative cancer therapy
Hydrogel
Antitumor immunity
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