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Mitochondrial Disruption Nanosystem Simultaneously Depressed Programmed Death Ligand-1 and Transforming Growth
Xin Jiang1,2, Lei Yi3, Cheng Li4
1Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Abstract:
Currently, limited photosensitizers possess the capacity to reverse tumor hypoxia and reduce programmed death ligand-1 (PD-L1) and transforming growth factor-β (TGF-β) expression simultaneously, hindering the perfect photodynamic therapy (PDT) effect due to acquired immune resistance and the tumor hypoxic microenvironment. To tackle these challenges, in this research, we demonstrated that mitochondrial energy metabolism depression can be utilized as an innovative and efficient approach for reducing the expression of PD-L1 and TGF-β simultaneously, which may offer a design strategy for a more ideal PDT nanosystem. Through proteomic analysis of 5637 cells, we revealed that tamoxifen (TMX) can incredibly regulate PD-L1 expression in tumor cells. Then, to selectively deliver clinically used mitochondrial energy metabolism depressant TMX to solid tumors as well as design an ideal PDT nanosystem, we synthesized MHI-TMX@ALB by combining a mitochondria-targeted heptamethine cyanine PDT-dye MHI with TMX through self-assembly with albumin (ALB). Interestingly enough, the MHI-TMX@ALB nanoparticle demonstrated effective reversion of tumor hypoxia and inhibition of PD-L1 protein expression at a lower dosage (7.5 times to TMX), which then enhanced the efficacy of photodynamic immunotherapy via enhancing T-cell infiltration. Apart from this, by leveraging the heptamethine dye's targeting capacity toward tumors and TMX's role in suppressing TGF-β, MHI-TMX@ALB also more effectively mitigated 4T1 tumor lung metastasis development. All in all, the MHI-TMX@ALB nanoparticle could be used as a multifunctional economical PD-L1 and TGF-β codepression immune-regulating strategy, broadening the potential clinical applications for a more ideal PDT nanosystem.
Insights
This study introduces a novel nanoparticle that reverses tumor hypoxia and reduces immune-suppressing factors, enhancing photodynamic therapy (PDT) and immunotherapy. The MHI-TMX@ALB nanoparticle effectively combats tumor growth and metastasis.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Tumor hypoxia and immunosuppressive factors like PD-L1 and TGF-β limit photodynamic therapy (PDT) efficacy.
- Acquired immune resistance and the tumor microenvironment pose significant challenges for effective cancer treatment.
Purpose of the Study:
- To develop a multifunctional nanosystem for simultaneously reversing tumor hypoxia and downregulating PD-L1 and TGF-β.
- To design an ideal PDT nanosystem by leveraging mitochondrial energy metabolism depression.
Main Methods:
- Synthesized MHI-TMX@ALB nanoparticles combining a PDT dye (MHI) with tamoxifen (TMX) via albumin (ALB) self-assembly.
- Utilized proteomic analysis to identify TMX as a regulator of PD-L1 expression.
- Evaluated nanoparticle efficacy in reversing tumor hypoxia, inhibiting PD-L1 and TGF-β, and enhancing anti-tumor immunity.
Main Results:
- MHI-TMX@ALB nanoparticles effectively reversed tumor hypoxia and inhibited PD-L1 expression at a lower TMX dosage.
- The nanoparticles enhanced photodynamic immunotherapy by increasing T-cell infiltration.
- MHI-TMX@ALB demonstrated significant mitigation of 4T1 tumor lung metastasis development.
Conclusions:
- Mitochondrial energy metabolism depression is a viable strategy for reducing PD-L1 and TGF-β, offering a design principle for advanced PDT nanosystems.
- MHI-TMX@ALB serves as a multifunctional, economical strategy for co-depressing PD-L1 and TGF-β, enhancing immune regulation.
- This approach broadens clinical applications for more effective PDT-based cancer therapies.
