Covalent LYTAC Enabled by DNA Aptamers for Immune Checkpoint Degradation Therapy DOI
Yuqing Li, Xueliang Liu, Lu Yu

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 1, 2023

Immune checkpoint blockade (ICB) therapy, while achieving tremendous clinical successes, still suffers from a low objective response rate in cancer treatment. As proof-of-concept study, we propose new immune degradation (ICD) therapy relying on lysosome-targeting chimera (LYTAC) to deplete programmed death ligand-1 (PD-L1) the tumor cell surface. Our designed chimeric aptamer one side targets lysosome-trafficking receptor, and other allows biorthogonal covalent-conjugation-reinforced specific binding of PD-L1. This covalent LYTAC is able hijack PD-L1 for lysosomal with greatly improved efficiency over its noncovalent counterpart complex vivo environment. Beyond abolishing PD-1/PD-L1 axis associated resistance, demonstrate first time that LYTAC-triggered could directly cause immunogenic apoptosis cells elicit tumor-specific responses, offering unparalleled advantages ICB antibody therapy. Remarkably, ICD achieves comparable or higher antitumor efficacy causing significantly less inflammatory injury compared antibody-based Moreover, can serve as general platform specifically degrading membrane-associated proteins, making it promising tool future applications. work presents novel molecular effective environments, valuable insights pushing DNA-based drugs toward

Language: Английский

The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes DOI Open Access
Sayali Onkar, Neil Carleton, Peter C. Lucas

et al.

Cancer Discovery, Journal Year: 2022, Volume and Issue: 13(1), P. 23 - 40

Published: Dec. 6, 2022

Breast cancer, the most common type of cancer affecting women, encompasses a collection histologic (mainly ductal and lobular) molecular subtypes exhibiting diverse clinical presentation, disease trajectories, treatment options, outcomes. Immunotherapy has revolutionized for some solid tumors but shown limited promise breast cancers. In this review, we summarize recent advances in our understanding complex interactions between tumor immune cells at cellular microenvironmental levels. We aim to provide perspective on opportunities future immunotherapy agents tailored specific features each subtype cancer. Although there are currently over 200 ongoing trials testing immunotherapeutics, such as immune-checkpoint blockade agents, these largely restricted triple-negative HER2+ primarily focus T cells. With rapid expansion new vitro, vivo, data, it is critical identify highlight challenges unique drive next generation treatments that harness system.

Language: Английский

Citations

130
A Polymeric Hydrogel to Eliminate Programmed Death-Ligand 1 for Enhanced Tumor Radio-Immunotherapy DOI
Wenhao Shen, Pei Pei,

Chonghai Zhang

et al.

ACS Nano, Journal Year: 2023, Volume and Issue: 17(23), P. 23998 - 24011

Published: Nov. 21, 2023

Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, cycling process constantly transports from inside to outside of cells, facilitating renewal and replenishment cancer cell membrane. Herein, we develop sodium alginate hydrogel consisting elesclomol-Cu galactose induce persistent cuproptosis, leading reduction for radio-immunotherapy colon tumors. First, prefabricated synthesized immobilizing elesclomol onto saccharide chain through coordination with bivalent copper ions (Cu2+), followed incorporation galactose. After implantation into tumors, this can be further cross-linked in presence physiological calcium (Ca2+), resulting formation controlled release elesclomol-Cu2+ (ES-Cu) The effectively induces oligomerization DLAT cuproptosis colorectal cells. Interestingly, radiation-induced upregulation abrogated hydrogel, releasing ES-Cu Consequently, sensitization radiotherapy immunotherapy significantly improved, prolonging survival tumor-bearing mice both local metastatic Our study introduces an approach combines radiotherapy.

Language: Английский

Citations

97
Insights from a 30-year journey: function, regulation and therapeutic modulation of PD1 DOI
Kenji Chamoto, Tomonori Yaguchi, Masaki Tajima

et al.

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 23(10), P. 682 - 695

Published: April 25, 2023

Language: Английский

Citations

95
O -GlcNAcylation promotes tumor immune evasion by inhibiting PD-L1 lysosomal degradation DOI Creative Commons
Qiang Zhu, Hongxing Wang, Siyuan Chai

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(13)

Published: March 21, 2023

Programmed-death ligand 1 (PD-L1) and its receptor programmed cell death (PD-1) mediate T cell-dependent immunity against tumors. The abundance of surface PD-L1 is a key determinant the efficacy immune checkpoint blockade therapy targeting PD-L1. However, regulation still poorly understood. Here, we show that lysosomal degradation regulated by O-linked N-acetylglucosamine (O-GlcNAc) during intracellular trafficking pathway. O-GlcNAc modifies hepatocyte growth factor-regulated tyrosine kinase substrate (HGS), component endosomal sorting machinery, subsequently inhibits interaction with PD-L1, leading to impaired inhibition activates cell-mediated antitumor in vitro immune-competent mice manner dependent on HGS glycosylation. Combination antibody synergistically promotes response. We also designed competitive peptide inhibitor glycosylation decreases expression enhances tumor cells. Collectively, our study reveals link between evasion, suggests strategies for improving PD-L1-mediated therapy.

Language: Английский

Citations

70
Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy DOI Creative Commons

Shuangneng Yin,

Zhaojun Chen, Dugang Chen

et al.

Theranostics, Journal Year: 2023, Volume and Issue: 13(5), P. 1520 - 1544

Published: Jan. 1, 2023

Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on forms of various regulating mechanisms to enhance therapeutic effect, including blockade interaction between PD-1, downregulation expression degradation mature PD-L1. Thereinto, describe variety materials been designed target PD-L1, antibodies, nanoparticle, peptide, aptamer, RNA, small molecule. Additionally, list drugs regulation capacity used in clinical ongoing studies explore other alternatives besides anti-PD-L1 monoclonal antibodies. Moreover, discuss associated opportunities cancer combination therapy modalities such as chemotherapy, radiotherapy, photodynamic (PDT) photothermal (PTT), these conventional or emerging capable increasing cells by altering microenvironment (TME), would display synergistic effect. At last, give brief summary outlook regarding research status future prospect immunotherapy.

Language: Английский

Citations

64
The complementarity of DDR, nucleic acids and anti-tumour immunity DOI

Anand Kornepati,

Cody M. Rogers, Patrick Sung

et al.

Nature, Journal Year: 2023, Volume and Issue: 619(7970), P. 475 - 486

Published: July 19, 2023

Language: Английский

Citations

53
Immune checkpoint receptors in autoimmunity DOI
Kelly P. Burke, Dillon G. Patterson, Dan Liang

et al.

Current Opinion in Immunology, Journal Year: 2023, Volume and Issue: 80, P. 102283 - 102283

Published: Jan. 28, 2023

Language: Английский

Citations

43
CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors DOI Creative Commons
Lei Peng, Giacomo Sferruzza,

Luojia Yang

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(10), P. 1089 - 1108

Published: Aug. 12, 2024

Abstract In the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach for combating cancers, demonstrating remarkable efficacy in relapsed/refractory hematological malignancies both pediatric and adult patients. CAR-natural killer (CAR-NK) complements CAR-T by offering several distinct advantages. CAR-NK cells do not require HLA compatibility exhibit low safety concerns. Moreover, are conducive to “off-the-shelf” therapeutics, providing significant logistic advantages over cells. Both have shown consistent results malignancies. However, their against solid tumors remains limited due various obstacles including tumor trafficking infiltration, well an immuno-suppressive microenvironment. this review, we discuss recent advances current challenges of immunotherapies, with specific focus on application tumors. We also analyze depth drawbacks compared highlight CAR optimization. Finally, explore future perspectives these adoptive highlighting increasing contribution cutting-edge biotechnological tools shaping next generation cellular immunotherapy.

Language: Английский

Citations

38
Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges DOI Creative Commons
Sadique A. Javed, Asim Najmi, Waquar Ahsan

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 10, 2024

The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes signal transduction of the receptor. This leads to suppression survival, proliferation, activity in tumor microenvironment resulting compromised anticancer immunity. PD-1/PD-L-1 blockade shown remarkable clinical success various cancer immunotherapies. To date, most blockers approved for use are monoclonal antibodies (mAbs); however, their therapeutic limited owing poor responses proportion patients. mAbs also displayed low penetration, steep production costs, incidences immune-related side effects. strongly indicates importance developing novel inhibitors immunotherapeutic agents. Recently, advancements small molecule-based (SMIs) that directly block axis gained attention from scientific community involved research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, cost, greater cell possibility oral administration. Currently, several development pipeline potential therapeutics immunotherapy. develop new SMIs, wide range structural scaffolds have been explored excellent outcomes; biphenyl-based studied. In this review, we analyzed targeting treatment. Altogether, present review delves into problems related detailed discussion on current status SMIs. article may provide comprehensive guide medicinal chemists regarding required inhibition.

Language: Английский

Citations

30
The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases DOI Creative Commons
Antero Salminen

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(6), P. 733 - 750

Published: April 11, 2024

Abstract The accumulation of senescent cells within tissues is a hallmark the aging process. Senescent are also commonly present in many age-related diseases and cancer microenvironment. escape abnormal from immune surveillance indicates that there some defect function cytotoxic cells, e.g., CD8 + T natural killer (NK) cells. Recent studies have revealed expression programmed death-ligand 1 (PD-L1) protein abundantly increased An increase amount PD-L1 protects clearance by PD-1 checkpoint receptor In fact, activation suppresses properties NK promoting state immunosenescence. inhibitory PD-1/PD-L1 pathway acts cooperation with immunosuppressive cells; for example, can enhance differentiation regulatory (Treg), myeloid-derived suppressor (MDSC), M2 macrophages, whereas cytokines secreted stimulate protein. Interestingly, signaling pathways known to promote cellular senescence process crucial stimulators protein, epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, AhR signaling. It seems axis has role thus it promotes tissues. Thus, blockade might be potential anti-aging senolytic therapy. Key messages accumulate during diseases. able Expression markedly increases Age-related stimulates Inhibitory

Language: Английский

Citations

23