Citation: Huanhui Wang, Longyi Nan, Yan Zheng, Jianpeng Guo, Guangchun Piao. HOF-based catalytic platform combining sonodynamic therapy and bioorthogonal activation of immunosuppression reversal for cancer therapy[J]. Chinese Chemical Letters, ;2026, 37(8): 111837. doi: 10.1016/j.cclet.2025.111837 shu

HOF-based catalytic platform combining sonodynamic therapy and bioorthogonal activation of immunosuppression reversal for cancer therapy

Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China

zhengyan_0308@163.com

gjp807@ybu.edu.cn

gcpiao@ybu.edu.cn

Received Date: 9 July 2025
Revised Date: 11 September 2025
Accepted Date: 12 September 2025
Available Online: 12 September 2025

Figures(5)

The combination of sonodynamic therapy (SDT) and immunotherapy exhibits potent anticancer efficacy. However, most sonosensitizers produce reactive oxygen species (ROS) with low efficiency under ultrasound (US). Chemotherapy-induced immunogenic cell death (ICD) is also plagued by toxic side effects, suboptimal efficacy, and immune escape. Herein, we developed a cancer therapy platform based on a sonosensitizer, iron porphyrin (Fe(Ⅲ) meso-tetra(4-carboxyphenyl)porphine chloride, FeTCPPCl), which self-assembles into a hydrogen-bonded organic framework (PHOF-1). This platform enables precise activation and spatiotemporal controlled release of prodrugs, thereby inducing ICD efficiently and safely. Specifically, PHOF-1 bioorthogonally activates the doxorubicin prodrug (pro-DOX) in situ, synergizing with sonodynamic immunotherapy. This strategy, which combines SDT with in situ prodrug activation, minimizes drug side effects and maximizes therapeutic effects. Additionally, this system activates the metformin (Glucophage) prodrug (pro-MET), with ATP depletion leading to upregulated adenosine monophosphate activated protein kinase (AMPK) expression, increased programmed death-ligand 1 (PD-L1) degradation, and reversal of tumor immunosuppression. Remarkably, SDT combined with bioorthogonal in situ immune activation represents a novel approach to enhance cancer immunotherapy. This synergy effectively converts "cold" tumors into "hot" tumors by promoting ICD and reducing PD-L1 expression, thereby improving immunotherapy efficacy. The integration of SDT and bioorthogonal chemistry offers a controllable therapeutic strategy with reduced immune-related adverse effects, providing a promising avenue for safer and more effective cancer immunotherapy through the induction of adaptive antitumor immunity.
- Sonodynamic,
- Hydrogen-bonded organic frameworks,
- Bioorthogonal reaction,
- Immunogenic cell death,
- Immune evasion
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