Dual pH-sensitive nanodrug blocks PD-1 immune checkpoint and uses T cells to deliver NF-κB inhibitor for antitumor immunotherapy

Xiao, Zecong; Su, Zhenwei; Han, Shisong; Huang, Jinsheng; Li, Lin; Shuai, Xintao

doi:10.1126/sciadv.aay7785

Cited by 126 publications

(102 citation statements)

References 42 publications

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“…A recent study by Xiao et al demonstrates that combined therapy of NF-κB inhibitor curcumin together with PD-1 blockade significantly improved antitumor immunotherapeutic effect both in vitro and in vivo. The treatment inhibited tumor growth and prolonged survival in a melanoma mouse model [122]. Interestingly, they applied both curcumin and anti-PD-1 monoclonal antibody (mAb) through nanotechnology.…”

Section: Natural Compoundsmentioning

confidence: 99%

“…Because of its pH sensitivity, the nanodrug is released in the acidic TME. On site, the nanodrug leaves anti-PD-1 mAb to block PD-1 on anti-tumor T cells and generates a new curcumin-encapsulated nanodrug that can be taken up by tumor cells or tumor associated macrophages [122]. The nanodrug has high therapeutic potential since it showed low side effects in vivo and can simultaneously restore tumor killing of cytotoxic T cells and inhibit the NF-κB pathway to recruit anti-tumor T cells into the TME.…”

Section: Natural Compoundsmentioning

confidence: 99%

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NF-κB and Its Role in Checkpoint Control

Betzler

Theodoraki

Schuler

et al. 2020

IJMS

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Nuclear factor-κB (NF-κB) has been described as one of the most important molecules linking inflammation to cancer. More recently, it has become clear that NF-κB is also involved in the regulation of immune checkpoint expression. Therapeutic approaches targeting immune checkpoint molecules, enabling the immune system to initiate immune responses against tumor cells, constitute a key breakthrough in cancer treatment. This review discusses recent evidence for an association of NF-κB and immune checkpoint expression and examines the therapeutic potential of inhibitors targeting either NF-κB directly or molecules involved in NF-κB regulation in combination with immune checkpoint blockade.

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Section: Natural Compoundsmentioning

confidence: 99%

Section: Natural Compoundsmentioning

confidence: 99%

NF-κB and Its Role in Checkpoint Control

Betzler

Theodoraki

Schuler

et al. 2020

IJMS

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“…Consistently, prolonged systemic inhibition of IKKβ by the Kinase Inhibitor of NF-κB-1 (KINK-1) agent, though ineffective when administered alone, potentiates the anti-cancer effect of a tumor vaccine in transplanted melanoma [87]. Another well-known, though poorly selective, IKK inhibitor, curcumin, decreases the number of intra-tumoral Treg cells in preclinical models of cancer [92][93][94], and enhances Th1 cells, while decreasing Treg cells in patients with lung and colon cancer [95,96]. Finally, c-Rel inhibition using the methylxanthine derivative Pentoxifylline (PTXF) or the selective c-Rel inhibitors, IT-603 or R96A, significantly reduces tumor growth and synergizes with anti-PD-1/Programed cell Death Ligand 1 (PD-L1) therapy as well as doxorubicin [26,[97][98][99].…”

Section: The Many Roles Of Nf-κb In Treg Cellsmentioning

confidence: 97%

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Stéphan¹,

Lautraite²,

Voisin³

et al. 2020

Cancers

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Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

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“…Target and deplete the TAMCs and attenuate immunosuppression [112] Antibody fragment PEG-PLGA nanoparticles Esterase TGF 1 inhibitor, TLR7/8 agonist Restore effector T-cell function by inhibiting the TGF 1 activity, recruit lymphocytes to noninflamed tumors [114] PD-1 Magnetic nanoclusters pH -Reverse immunosuppress of tumor [120] PD-1 Dual pH-sensitive PDPA nanoparticles pH CUR (NF-B inhibitor) Combination of PD-1 blockade and NF-B inhibition [122] PD-1, CTLA-4 TfR or angiopep-2 peptide modified biopolymer scaffold…”

Section: Nlg919mentioning

confidence: 99%

Engineering Prodrug Nanomedicine for Cancer Immunotherapy

et al. 2020

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Immunotherapy has shifted the clinical paradigm of cancer management. However, despite promising initial progress, immunotherapeutic approaches to cancer still suffer from relatively low response rates and the possibility of severe side effects, likely due to the low inherent immunogenicity of tumor cells, the immunosuppressive tumor microenvironment, and significant interand intratumoral heterogeneity. Recently, nanoformulations of prodrugs have been explored as a means to enhance cancer immunotherapy by simultaneously eliciting antitumor immune responses and reversing local immunosuppression. Prodrug nanomedicines, which integrate engineering advances in chemistry, oncoimmunology, and material science, are rationally designed through chemically modifying small molecule drugs, peptides, or antibodies to yield increased bioavailability and spatiotemporal control of drug release and activation at the target sites. Such strategies can help reduce adverse effects and enable codelivery of multiple immune modulators to yield synergistic cancer immunotherapy. In this review article, recent advances and translational challenges facing prodrug nanomedicines for cancer immunotherapy are overviewed. Last, key considerations are outlined for future efforts to advance prodrug nanomedicines aimed to improve antitumor immune responses and combat immune tolerogenic microenvironments.

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Dual pH-sensitive nanodrug blocks PD-1 immune checkpoint and uses T cells to deliver NF-κB inhibitor for antitumor immunotherapy

Cited by 126 publications

References 42 publications

NF-κB and Its Role in Checkpoint Control

NF-κB and Its Role in Checkpoint Control

Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

Engineering Prodrug Nanomedicine for Cancer Immunotherapy

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