Heterocyclic-Modified Imidazoquinoline Derivatives: Selective TLR7 Agonist Regulates Tumor Microenvironment against Melanoma DOI
Jiaxin Ou, Lu Zheng, Yanlin Chen

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(5), P. 3321 - 3338

Published: Feb. 16, 2024

Immunotherapy targeting the toll-like receptor 7 (TLR7) is a promising strategy for cancer treatment. Herein, we describe design and synthesis of series imidazoquinoline-based TLR7 agonists assess NF-κB pathway activation using HEK-Blue hTLR7 cells to identify most potent small-molecule agonist, SMU-L11 (EC50 = 0.024 ± 0.002 μM). In vitro experiments demonstrated that specifically activated TLR7, resulting in recruitment MyD88 adaptor protein MAPK signaling pathways. Moreover, was found exert immune-enhancing effects by significantly inducing secretion proinflammatory cytokines murine dendritic cells, macrophages, human peripheral blood mononuclear while promoting M1 macrophage polarization. vivo studies B16-F10 mouse tumor model showed enhanced immune cell augmented CD4+ T CD8+ T-cell proliferation, directly killing inhibiting growth.

Language: Английский

Rational combinations of targeted cancer therapies: background, advances and challenges DOI
Haojie Jin, Liqin Wang, René Bernards

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 22(3), P. 213 - 234

Published: Dec. 12, 2022

Language: Английский

Citations

246
Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy DOI Creative Commons
Yujia Chen, Guan-Nan Li,

Xian-Jing Li

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(17)

Published: April 28, 2023

Immune-responsive gene 1 (IRG1) encodes aconitate decarboxylase (ACOD1) that catalyzes the production of itaconic acids (ITAs). The anti-inflammatory function IRG1/ITA has been established in multiple pathogen models, but very little is known cancer. Here, we show IRG1 expressed tumor-associated macrophages (TAMs) both human and mouse tumors. Mechanistically, tumor cells induce Irg1 expression by activating NF-κB pathway, ITA produced ACOD1 inhibits TET DNA dioxygenases to dampen inflammatory genes infiltration CD8+ T into sites. Deletion mice suppresses growth types enhances efficacy anti-PD-(L)1 immunotherapy. Our study provides a proof concept potential target for immune-oncology drugs IRG1-deficient represent potent cell therapy strategy cancer treatment even pancreatic tumors are resistant cell-based

Language: Английский

Citations

84
Organic Sonodynamic Materials for Combination Cancer Immunotherapy DOI
Chi Zhang, Kanyi Pu

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(51)

Published: June 1, 2023

Sonodynamic therapy (SDT) is a promising non-invasive therapeutic modality to treat deep-seated tumors owing the good tissue penetration ability and spatiotemporal controllability of ultrasound (US); however, low sonodynamic activity potential side effects greatly limit its clinical translation. Cancer immunotherapy that leverages immune system fight against cancer has great synergize with SDT for treatment high efficiency safety. In this review, convergence exert their merits break through limitations combination sono-immunotherapy are discussed. The focus on development construction organic materials immunotherapeutic efficiency. These not only induce immunogenic cell death improve tumor immunogenicity via but also activate antitumor immunity immuno-oncology drug-mediated pathway modulation. various drugs sonosensitizers categorized discussed along prospects challenges

Language: Английский

Citations

72
Small molecule-based immunomodulators for cancer therapy DOI Creative Commons

Yinrong Wu,

Zichao Yang, Kui Cheng

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2022, Volume and Issue: 12(12), P. 4287 - 4308

Published: Nov. 12, 2022

Immunotherapy has led to a paradigm shift in the treatment of cancer. Current cancer immunotherapies are mostly antibody-based, thus possessing advantages regard pharmacodynamics (e.g., specificity and efficacy). However, they have limitations terms pharmacokinetics including long half-lives, poor tissue/tumor penetration, little/no oral bioavailability. In addition, therapeutic antibodies immunogenic, may cause unwanted adverse effects. Therefore, researchers shifted their efforts towards development small molecule-based immunotherapy, as molecules overcome above disadvantages associated with antibodies. Further, immunomodulators complementary modalities for treatment, be combined elicit synergistic Recent years witnessed rapid immunotherapy. this review, we describe current progress (inhibitors/agonists/degraders) therapy, those targeting PD-1/PD-L1, chemokine receptors, stimulator interferon genes (STING), Toll-like receptor (TLR), etc. The tumorigenesis mechanism various targets respective modulators that entered clinical trials also summarized.

Language: Английский

Citations

70
The hallmarks of cancer immune evasion DOI
Claudia Galassi, Timothy A. Chan, Ilio Vitale

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(11), P. 1825 - 1863

Published: Oct. 10, 2024

Language: Английский

Citations

70
NK cell-based tumor immunotherapy DOI Creative Commons
Hao Zhang, Yang Li, Tingting Wang

et al.

Bioactive Materials, Journal Year: 2023, Volume and Issue: 31, P. 63 - 86

Published: Aug. 9, 2023

Natural killer (NK) cells display a unique inherent ability to identify and eliminate virus-infected tumor cells. They are particularly powerful for elimination of hematological cancers, have attracted considerable interests therapy solid tumors. However, the treatment tumors with NK less effective, which can be attributed very complicated immunosuppressive microenvironment that may lead inactivation, insufficient expansion, short life, poor infiltration Fortunately, development advanced nanotechnology has provided potential solutions these issues, could improve immunotherapy efficacy In this review, we summarize activation inhibition mechanisms in tumors, recent advances cell-based boosted by diverse nanomaterials. We also propose challenges opportunities clinical application immunotherapy.

Language: Английский

Citations

46
H3K18 Lactylation Potentiates Immune Escape of Non-Small Cell Lung Cancer DOI
Zhang Cai, Lijie Zhou,

Mingyuan Zhang

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(21), P. 3589 - 3601

Published: Aug. 13, 2024

Abstract Recently discovered epigenetic modification lysine lactylation contributes to tumor development and progression in several types of cancer. In addition the tumor-intrinsic effects, histone may mediate microenvironment remodeling immune evasion. this study, we observed elevated pan–lysine H3 18 (H3K18la) levels non–small cell lung cancer (NSCLC) tissues, which was positively correlated with poor patient prognosis. Interruption glycolysis by 2-deoxy-D-glucose oxamate treatment silencing lactate dehydrogenase A B reduced H3K18la circumvented evasion NSCLC cells enhancing CD8+ T-cell cytotoxicity. Mechanistically, directly activated transcription pore membrane protein 121 (POM121), enhanced MYC nuclear transport direct binding CD274 promoter induce PD-L1 expression. a mouse xenograft model, combination therapy inhibitor an anti-PD-1 antibody induced intratumoral function exhibited strong antitumor efficacy. Overall, work revealed that potentiates escape activating POM121/MYC/PD-L1 pathway, offers insights into role posttranslational modifications carcinogenesis provides rationale for developing epigenetic-targeted strategy treating NSCLC. Significance: H3K18 supports immunosuppression non-small inducing POM121 increase activity expression, can be reversed metabolic reprogramming immunotherapy treatment.

Language: Английский

Citations

32
Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1 DOI Creative Commons
W. Ren, Zilong Xu, Yating Chang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Abstract PD-1 is a co-inhibitory receptor expressed by CD8 + T cells which limits their cytotoxicity. PD-L1 expression on cancer contributes to immune evasion cancers, thus, understanding the mechanisms that regulate protein levels in cancers important. Here we identify tumor-cell-expressed otubain-2 (OTUB2) as negative regulator of antitumor immunity, acting through PD-1/PD-L1 axis various human cancers. Mechanistically, OTUB2 directly interacts with disrupt ubiquitination and degradation endoplasmic reticulum. Genetic deletion markedly decreases proteins tumor cell surface, resulting increased sensitivity T-cell-mediated To underscore relevance patients, observe significant correlation between abundance non-small lung cancer. An inhibitor OTUB2, interfering its deubiquitinase activity without disrupting OTUB2-PD-L1 interaction, successfully reduces suppressed growth. Together, these results reveal roles regulation lays down proof principle for targeting therapeutic strategy treatment.

Language: Английский

Citations

18
Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer DOI Creative Commons

Yixiang Gu,

Ruifeng Yang, Yang Zhang

et al.

Molecular Biomedicine, Journal Year: 2025, Volume and Issue: 6(1)

Published: Jan. 6, 2025

Cancer remains a leading cause of mortality globally and major health burden, with chemotherapy often serving as the primary therapeutic option for patients advanced-stage disease, partially compensating limitations non-curative treatments. However, emergence resistance significantly limits its efficacy, posing clinical challenge. Moreover, heterogeneity mechanisms across cancer types complicates development universally effective diagnostic approaches. Understanding molecular chemoresistance identifying strategies to overcome it are current research focal points. This review provides comprehensive analysis key underlying resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular metabolism, role stem cells (CSCs). We also examine specific causes in highlight various targets involved resistance. Finally, we discuss aiming at overcoming such combination therapies, targeted treatments, novel delivery systems, while proposing future directions this evolving field. By addressing these barriers, lays foundation more therapies aimed mitigating

Language: Английский

Citations

6
Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways DOI Creative Commons
Zhi Zhu, A. J. Robert McGray, Weijian Jiang

et al.

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Oct. 11, 2022

Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness OV as monotherapy remains limited, and thus investigators have been exploring various combinations other anti-cancer agents demonstrated improved As cancer cells evolved alter signaling pathways enhanced cell proliferation, progression metastasis, these cellular molecular changes offer promising targets rational therapy design. In this regard, molecules in relevant or/and immune cells, such EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, epigenetic, or histone deacetylases, cGAS-STING) are currently under investigation potential synergize modulate milieu tumor microenvironment (TME), thereby improving sustaining immunity. many small molecule modulators developed shown strong potential, here we review findings related both OV-mediated immunotherapy utility immuno-oncology. Then, focus on discussion rationales strategies combining selected targeting TME enhance Finally, provide perspectives viewpoints application novel experimental systems technologies that can propel exciting branch medicine into bright future.

Language: Английский

Citations

60