Mitochondrial Disruption Nanosystem Simultaneously Depressed Programmed Death Ligand-1 and Transforming Growth Factor-β to Overcome Photodynamic Immunotherapy Resistance

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.