programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) axis regulation has presented impressive therapeutic efficacy against multiple types of cancers by enhancing T cell infiltration and revitalizing exhausted cytotoxic T cells, which finally shifted the paradigm of cancer management. [1] However, although the current clinically approved and used anti-PD-L1 monoclonal antibodies are effective in the treatment of many cancer types, their widespread usage is still limited and risky owing to immune-related adverse effects, insufficient tumor specificity, and high cost. [2] Moreover, most anti-PD-L1 monoclonal antibodies could only disrupt the PD-1/ PD-L1 axis recognition on the surfaces of T cells and cancer cells, without taking into account the immune-regulation capacity of the cytoplasm or the nucleus distributed PD-L1 protein, which also seriously limited the efficacy of radioimmunotherapy and chemoimmunotherapy when combined with anti-PD-L1 monoclonal antibodies since anti-PD-L1 monoclonal antibodies could not influence the cytoplasm or the nucleus distributed PD-L1 protein and its mediated increased DNA damage repair. [3] Thus, there is still a need to better understand the mechanisms of regulating the PD-L1/PD-1 axis to augment approaches that target this pathway.Currently, the role of the lysosome, endoplasmic reticulum, or dictyosome in the transcription and translation of programmed cell death ligand 1 (PD-L1) is well revealed, but the role and function of mitochondria in the PD-L1 expression in tumors is still not fully researched, making it hard to offer a novel PD-L1 regulation strategy. In this research, it is newly revealed that mitochondria oxidative phosphorylation (OXPHOS) depression can be used as an effective PD-L1 down-regulation method. To offer an ideal and higheffective tumor mitochondria-targeted OXPHOS depression nanosystem, IR-LND is prepared by conjugating mitochondria-targeted heptamethine cyanine dye IR-68 with mitochondrial complexes I and II depression agent lonidamine (LND), which then further self-assembled with albumin (Alb) to form IR-LND@Alb nanoparticles. By doing this, PD-L1 expression in tumors is selectively and effectively depressed by IR-LND@Alb nanoparticles. As expected, the anti-tumor efficacy of such a PD-L1 depression strategy is superior to conventional anti-PD-L1 monoclonal antibodies. Interestingly, IR-LND can also be served as a novel ideal promising photodynamic therapy (PDT) drug with self-oxygen and self-PD-L1 regulation capacity. All in all, this tumorselective metabolic reprogramming platform to reactivate immunotherapy and sensitize for PDT effect, would open a new window for mitochondrial immunotherapy for cancer patients.
Combined
therapy provides a more effective method in the treatment
of tumors and becomes a research hotspot. To improve treatment outcomes
and reduce serious side effects, hydrogel-based local delivery was
developed herein to form a drug depot in suit to eliminate tumors.
Indocyanine green and imiquimod were coencapsulated in the novel temperature-sensitive
chitosan hydrogel. After intratumoral injection of the hydrogel, indocyanine
green that accumulated in the tumor area could induce thermal ablation
of primary tumors under laser irradiation. In the presence of imiquimod,
the immune effects increased the probability of complete ablation
of primary tumors and inhibition of metastases. Combined with cyclophosphamide,
the enhanced immunological responses would further inhibit tumors
and prolong the survival time. In a word, this work offered an excellent
local delivery platform that enabled a remarkable combined antitumor
strategy and achieved synergistic therapeutic effects.
Background
Mild-temperature photothermal therapy (mild-PTT) has emerged as a highly promising antitumor strategy by triggering immunogenic cell death (ICD) to elicit both innate and adaptive immune responses for tumor control. However, mild-PTT still leads to the risk of tumor recurrence or metastasis because it could hardly completely eradicate tumors due to its impaired immunological efficacy owing to the enhanced PD-L1 expression in tumor cells after treatment.
Results
In this study, we described a hydrogen peroxide (H2O2) responsive manganese dioxide mineralized albumin nanocomposite loading with mitochondria function inhibitor phenformin (PM) and near-infrared photothermal dye indocyanine green (ICG) by modified two-step biomineralization method. In combination with ICG induced mild-PTT and PM mediated mitochondria dysfunction, PD-L1 expression was obviously down-regulated and the generated immunological responses was able to effectively attack the remaining tumor cells. Meanwhile, the risk of tumor metastasis was effectively inhibited by reducing the expression of tumor invasion-related signal molecules (TGF-β and vimentin) after combining treatment.
Conclusion
Such a strategy offers novel insight into the development of nanomedicine for mild-PTT as well as cancer immunotherapy, which can provide protection against tumor relapse post elimination of their initial and metastatic tumors.
Graphical Abstract
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