# Dual Sensitization Enables Synergistic Photodynamic Therapy and Radiotherapy for Breast Cancer

## TL;DR

A new nanoplatform improves photodynamic and radiotherapy for breast cancer by reducing tumor hypoxia and boosting treatment effectiveness.

## Contribution

A folate-modified copper-doped carbon dot nanoplatform synergizes photodynamic therapy and radiotherapy by remodeling the tumor microenvironment.

## Key findings

- FCA reduced 4T1 cell viability to 20.09% and induced 83.82% apoptosis.
- FCA-PDT-RT achieved superior tumor control at 12 Gy with increased T cell infiltration and suppressed angiogenesis.
- The treatment caused metabolic crisis through redox and energy collapse in cancer cells.

## Abstract

Radiotherapy (RT) and photodynamic therapy (PDT) for breast cancer are limited by tumor hypoxia and suboptimal photosensitizer performance. We developed folate-modified copper-doped carbon dots and loaded them with 5-aminolevulinic acid (ALA) to yield FCA, a nanoplatform that executes cascade nanozyme activities to remodel the tumor microenvironment: decomposing H2O2 to relieve hypoxia, generating hydroxyl radicals and singlet oxygen (1O2), and depleting glutathione (GSH). This priming enabled efficient ALA-to-protoporphyrin IX conversion, which subsequently amplified reactive oxygen species generation. The elevated oxidative stress then synergized with RT to accumulate DNA double-strand breaks and trigger cell cycle arrest. Consequently, FCA-PDT-RT reduced 4T1 cell viability to 20.09% and induced 83.82% apoptosis outcomes mechanistically linked to nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1)–heme oxygenase 1 (HMOX1) pathway activation. Despite compensatory upregulation of antioxidant genes (HMOX1 and glutamate–cysteine ligase modifier subunit [GCLM]), intracellular GSH and adenosine triphosphate were severely depleted, establishing a metabolic crisis wherein synthesis could not match consumption. This redox/energy collapse drove the pronounced cytotoxicity observed. In an orthotopic 4T1 model, FCA-PDT-RT achieved superior tumor control at only 12 Gy, which correlated with increased CD3+/CD8+ T cell infiltration and suppressed angiogenesis, while maintaining favorable safety. FCA thus enables synergistic PDT-RT through sequential microenvironment remodeling, oxidative amplification, and metabolic exhaustion, offering a dose-sparing strategy with translational promise for breast cancer therapy.