Tumor Selective Metabolic Reprogramming as a Prospective PD‐L1 Depression Strategy to Reactivate Immunotherapy

Abstract

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.

Cytotoxic Effects of Combinative ZnPcS4 Photosensitizer Photodynamic Therapy (PDT) and Cannabidiol (CBD) on a Cervical Cancer Cell Line

“…Clinically, most treatments used for cancers induce higher expressions of programmed cell death ligand 1 (PD-L1), which impairs the efficacy of anti-cancer drugs [ 59 ], including PDT. Moreover, it has recently been discovered that the cytoplasm or nucleus-distributed PD-L1 protein may also detrimentally limit the efficacy of certain therapies by increasing DNA damage repair [ 60 ]. Interestingly, recent experimentation has revealed that certain PDT PSs, when coupled with appropriate anti-tumor agents, can potentially overcome the challenges of PD-L1 up-regulation and tumor hypoxia in PDT, and so ultimately improve treatment outcomes [ 60 ].…”

Advancements in Cancer Immunotherapies

“…Interestingly, the anti-tumor efficacy of the PD-L1 depression strategy was found to be superior to the conventional anti-PD-L1 therapy in terms of selectivity and efficacy. This group has developed a mitochondria-oxidative phosphorylation (OXPHOS) depression nanosystem using IR-LND (conjugate of mitochondria-targeted heptamethine cyanine dye IR-68 with mitochondrial complexes I and II depression agent lonidamine (LND)) assembled with albumin (Alb) to form IR-LND@Alb nanoparticles [ 55 ]. Another promising therapy that has the same limitation of causing severe hypoxia and PD-L1 over-expressed immunosuppressed TME is photodynamic therapy (PDT).…”

Hydrogel systems for targeted cancer therapy

“…However, traditional therapies often pose problems such as major adverse reactions, low treatment efficiency, poor tolerance, and low targeting, causing great damage to normal cells while killing cancer cells ( Chrysostomou et al, 2022 ; Feng et al, 2022 ; Xiao and Zhuang, 2022 ). The advent of immunotherapy, hyperthermia, photothermal therapy, and photodynamic therapy has greatly enriched the treatment options for cancer and led to a paradigm shift from conventional treatment to a comprehensive sequential treatment model ( Boshuizen and Peeper, 2020 ; Liu et al, 2022a ). Both active immunotherapy using cancer vaccines and passive immunotherapy using intrinsically anti-cancer active ingredients can recognise and reduce cancer cells by activating the body's own powerful immune cells, which is one of the most promising strategies to inhibit the metastasis and recurrence of various cancers ( Lin et al, 2022 ).…”