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Updated: Jun 16, 2026
Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Mitochondria-targeted photodynamic nanoparticles boost antitumor immunity by suppressing mitophagy in osteosarcoma
Qing Deng1,2, Jinsong Li1, Zhaochen Tong1
1Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, PR China.
Abstract:
Osteosarcoma (OS) responds poorly to immunotherapy owing to its highly immunosuppressive phenotype. Photodynamic therapy (PDT) can induce mitochondrial damage by generating reactive oxygen species (ROS), thereby triggering immunogenic cell death (ICD) and activating antitumor immunity. However, mitochondrial damage readily activates mitophagy, which attenuates oxidative stress and compromises therapeutic efficacy. In this study, we construct a multifunctional nanoparticle (TPSM@IT-4Cl), which co-loads the photosensitizer IT-4Cl and the mitochondrial fission inhibitor Mdivi-1 and can target mitochondria. TPSM@IT-4Cl is selectively delivered to the mitochondria of tumor cells and releases drugs in a glutathione (GSH)-responsive manner within a high-GSH microenvironment. Under localized light irradiation, TPSM@IT-4Cl efficiently generates ROS via IT-4Cl to induce mitochondrial damage, while the released Mdivi-1 inhibits mitochondrial fission and thereby indirectly interferes with mitophagy, ultimately amplifying the efficacy of PDT. Both in vitro and in vivo studies indicated that the resulting ICD remodels the tumor immune microenvironment and elicits potent anti-tumor immunity. Moreover, TPSM@IT-4Cl exhibits significant antitumor efficacy in OS patient-derived xenograft (PDX) models, highlighting its translational potential. Collectively, we developed a mitochondria-targeted photodynamic nanoparticle with concomitant mitophagy inhibition, which may provide a feasible strategy to overcome the limitations of immunotherapy in OS.
Insights
This study developed a novel nanoparticle to enhance photodynamic therapy (PDT) for osteosarcoma (OS) by targeting mitochondria and inhibiting mitophagy, leading to potent anti-tumor immunity and improved therapeutic efficacy.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Immunotherapy
Background:
- Osteosarcoma (OS) exhibits a highly immunosuppressive tumor microenvironment, limiting the effectiveness of immunotherapy.
- Photodynamic therapy (PDT) can induce immunogenic cell death (ICD) and activate anti-tumor immunity, but its efficacy is often compromised by mitophagy, a process that removes damaged mitochondria.
Purpose of the Study:
- To develop a mitochondria-targeted nanoparticle that enhances PDT efficacy in OS by inhibiting mitophagy.
- To investigate the potential of this nanoparticle to overcome immunotherapy resistance in osteosarcoma.
Main Methods:
- Construction of a multifunctional nanoparticle (TPSM@IT-4Cl) co-loading a photosensitizer (IT-4Cl) and a mitochondrial fission inhibitor (Mdivi-1).
- Selective delivery of TPSM@IT-4Cl to tumor cell mitochondria, with glutathione (GSH)-responsive drug release.
- In vitro and in vivo evaluation of ROS generation, ICD induction, mitophagy inhibition, and anti-tumor immune response.
Main Results:
- TPSM@IT-4Cl efficiently generates ROS upon light irradiation, inducing mitochondrial damage and ICD.
- Co-delivery of Mdivi-1 inhibits mitophagy, amplifying PDT-induced anti-tumor immunity.
- Significant anti-tumor efficacy was observed in osteosarcoma patient-derived xenograft (PDX) models.
Conclusions:
- The developed mitochondria-targeted photodynamic nanoparticle with mitophagy inhibition offers a promising strategy to enhance immunotherapy for osteosarcoma.
- This approach holds translational potential for treating OS by overcoming its immunosuppressive nature.
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