posted on 2024-01-16, 19:57authored byXin Jiang, Lei Yi, Cheng Li, Haoxiang Wang, Wei Xiong, Yuan Li, Zaigang Zhou, Jianliang Shen
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.