Taming interleukin‐12: Engineering of bispecific antibody‐based IL‐12 mimetics with biased agonism capacities DOI Creative Commons
Britta Lipinski,

Laura Unmuth,

Paul Arras

et al.

Protein Science, Journal Year: 2025, Volume and Issue: 34(3)

Published: Feb. 21, 2025

In this work, we have generated bispecific interleukin (IL)-12 surrogate agonists based on camelid-derived single-domain antibodies (sdAbs) targeting the IL-12 receptor (IL-12R) subunits IL-12Rβ1 and IL-12Rβ2. Following immunization antibody display-based paratope isolation, respective sdAbs were combinatorially reformatted into a monovalent architecture by grafting resulting paratopes onto hinge region of heterodimeric Fc region. Functional characterization using NK-92 cells enabled identification multiple different sdAb-based bispecifics displaying divergent IL-12R agonism capacities as analyzed STAT4 phosphorylation. Further investigations harnessing peripheral blood mononuclear (PBMCs) from healthy donors revealed attenuated pSTAT4 activation compared to recombinant human (rh) wild-type regarding both natural killer (NK)-cell T-cell but robust stimulated T cells. While several mimetics nearly inactive NK well obtained PBMCs, they elicited significant phosphorylation interferon (IFN)-γ release an IL-12-like transcriptional signature. Furthermore, demonstrate that activity can also be biased towards changing spatial orientation individual within molecular design architecture. Taken together, present alternative strategy generate biologics with tailor-made characteristics.

Language: Английский

Inflammation in cancer: therapeutic opportunities from new insights DOI Creative Commons
Yifei Xie, Fangfang Liu, Yunfei Wu

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Feb. 24, 2025

As one part of the innate immune response to external stimuli, chronic inflammation increases risk various cancers, and tumor-promoting is considered enabling characteristics cancer development. Recently, there has been growing evidence on role anti-inflammation therapy in prevention treatment. And researchers have already achieved several noteworthy outcomes. In review, we explored underlying mechanisms by which affects occurrence development cancer. The pro- or anti-tumor effects these inflammatory factors such as interleukin, interferon, chemokine, inflammasome, extracellular matrix are discussed. Since FDA-approved drugs like aspirin show obvious effects, unique advantages due their relatively fewer side with long-term use compared chemotherapy drugs. make them promising candidates for chemoprevention. Overall, this review discusses molecules carcinogenesis new molecules-directed therapeutic opportunities, ranging from cytokine inhibitors/agonists, inflammasome inhibitors, some inhibitors that expected be applied clinical practice, well recent discoveries effect non-steroidal anti-inflammatory steroidal disadvantages application chemoprevention also

Language: Английский

Citations

2
Single-cell transcriptomics unveils multifaceted immune heterogeneity in early-onset versus late-onset cervical cancer DOI Creative Commons
Qian Chen,

Dongfeng Deng,

Hong Zhu

et al.

World Journal of Surgical Oncology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 14, 2025

Early-onset (EOCC) and late-onset cervical cancers (LOCC) represent two clinically distinct subtypes, each defined by unique clinical manifestations therapeutic responses. However, their immunological profiles remain poorly explored. Herein, we analyzed single-cell transcriptomic data from 4 EOCC LOCC samples to compare immune architectures. Epithelial cells in exhibited a notable dual phenotype, characterized immune-suppressive properties driven elevated CXCL production, alongside immune-stimulatory features linked heightened HLA molecule expression. CD4 + CD8 T demonstrated activation state, while NK diminished cytotoxicity. Macrophages displayed enhanced polarization towards both M1 M2 phenotypes, along with dendritic showing augmented antigen-presenting capacity. Regarding cancer-associated fibroblasts (CAFs), was enriched inflammatory CAFs, whereas harbored higher proportion of CAFs. These findings reveal the multifaceted heterogeneity between LOCC, underscoring imperative for age-tailored immunotherapeutic strategies.

Language: Английский

Citations

1
Targeting Cytokine-Mediated Inflammation in Brain Disorders: Developing New Treatment Strategies DOI Creative Commons
Rahul Mallick, Sanjay Basak, Parimal Chowdhury

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 104 - 104

Published: Jan. 15, 2025

Cytokine-mediated inflammation is increasingly recognized for playing a vital role in the pathophysiology of wide range brain disorders, including neurodegenerative, psychiatric, and neurodevelopmental problems. Pro-inflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) cause neuroinflammation, alter function, accelerate disease development. Despite progress understanding these pathways, effective medicines targeting are still limited. Traditional anti-inflammatory immunomodulatory drugs peripheral inflammatory illnesses. Still, they face substantial hurdles when applied to central nervous system (CNS), blood-brain barrier (BBB) unwanted systemic effects. This review highlights developing treatment techniques modifying cytokine-driven focusing on advances that selectively target critical involved pathology. Novel approaches, cytokine-specific inhibitors, antibody-based therapeutics, gene- RNA-based interventions, sophisticated drug delivery systems like nanoparticles, show promise with respect lowering neuroinflammation greater specificity safety. Furthermore, developments biomarker discoveries neuroimaging improving our ability monitor responses, allowing more accurate personalized regimens. Preclinical clinical trial data demonstrate therapeutic potential tailored techniques. However, significant challenges remain, across BBB reducing off-target As research advances, creation personalized, cytokine-centered therapeutics has therapy landscape illnesses, giving patients hope better results higher quality life.

Language: Английский

Citations

1
Distinct Immunophenotypic Profiles and Neutrophil Heterogeneity in Colorectal Cancer DOI

Minghua Bai,

Yuzhao Jin,

Zihao Jin

et al.

Cancer Letters, Journal Year: 2025, Volume and Issue: 616, P. 217570 - 217570

Published: Feb. 22, 2025

Language: Английский

Citations

1
Tumor Microenvironment and Cancer Metastasis DOI Creative Commons
Yulong Li, Han Wu

IntechOpen eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

The tumor microenvironment is a complex ecosystem composed of diverse cell types, extracellular matrix components, growth factors, and cytokines. dynamic interactions within this not only facilitate but also contribute to the establishment metastatic niches in distant organs. Furthermore, presence specific TME components can either promote or inhibit cancer migration, underscoring importance targeting these elements therapeutic strategies. This review seeks elucidate critical influence on metastasis examines potential targeted approaches. By integrating recent research insights, offers thorough understanding interplay between metastasis, serving as valuable reference for future investigations.

Language: Английский

Citations

1
Simultaneous co-delivery of Ginsenoside Rg3 and Imiquimod from PLGA nanoparticles for effective breast cancer immunotherapy DOI Creative Commons
Cong Hu,

S H Nong,

Qianqian Ke

et al.

iScience, Journal Year: 2025, Volume and Issue: 28(5), P. 112274 - 112274

Published: March 22, 2025

Breast cancer is a fatal malignancy facing human health, with most patients experiencing recurrence and resistance to chemotherapy. The immunosuppressive tumor microenvironment (TME) greatly limits the actual outcome of immunotherapy. This study aimed develop modality theranostics nanoparticles for breast based on near-infrared light-triggered nanoparticle targeted delivery ginsenoside Rg3 immune adjuvants imiquimod (R837) effective Folate-receptor (FA) targeting IR780-R837/ginsenoside Rg3-perfluorohexane (PFH) @ polyethylene glycol (PEG)-poly (lactide-co-glycolic acid) (PLGA) (FA-NPs) can be activated by laser irradiation in tumors, which leads rapid release R837 regions high expression folate receptors glucose transporter 1 (GLUT1). Meanwhile, used as dual-mode contrast agents photoacoustic ultrasound imaging. strategy provides strong memory effect, prevent after eliminating initial tumor.

Language: Английский

Citations

1
The Role of Inflammation in Cancer: Mechanisms of Tumor Initiation, Progression, and Metastasis DOI Creative Commons
Atsushi Nishida, Akira Andoh

Cells, Journal Year: 2025, Volume and Issue: 14(7), P. 488 - 488

Published: March 25, 2025

Inflammation is an essential component of the immune response that protects host against pathogens and facilitates tissue repair. Chronic inflammation a critical factor in cancer development progression. It affects every stage tumor development, from initiation promotion to invasion metastasis. Tumors often create inflammatory microenvironment induces angiogenesis, suppression, malignant growth. Immune cells within interact actively with cells, which drives progression through complex molecular mechanisms. triggered by factors such as infections, obesity, environmental toxins strongly linked increased risk. However, acute responses can sometimes boost antitumor immunity; thus, presents both challenges opportunities for therapeutic intervention. This review examines how contributes biology, emphasizing its dual role tumorigenesis potential target.

Language: Английский

Citations

1
PANCREATIC NEUROENDOCRINE NEOPLASMS (pNENs): GENETIC AND ENVIRONMENTAL BIOMARKERS FOR RISK OF OCCURRENCE AND PROGNOSIS DOI
Matteo Tacelli, Manuel Gentiluomo,

Paolo Biamonte

et al.

Seminars in Cancer Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

1
The Impact of Oral Microbiome Dysbiosis on the Aetiology, Pathogenesis, and Development of Oral Cancer DOI Open Access
Jasminka Talapko,

Suzana Erić,

Tomislav Meštrović

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(17), P. 2997 - 2997

Published: Aug. 28, 2024

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Although oral cavity an easily accessible area for visual examination, OSCC more often detected at advanced stage. The global prevalence of around 6%, with increasing trends posing a significant health problem due to increase in morbidity mortality. microbiome has been target numerous studies, findings highlighting role dysbiosis developing OSCC. Dysbiosis can significantly pathobionts (bacteria, viruses, fungi, parasites) that trigger inflammation through their virulence pathogenicity factors. In contrast, chronic bacterial contributes development Pathobionts also have other effects, such as impact on immune system, which alter responses contribute pro-inflammatory environment. Poor hygiene carbohydrate-rich foods risk factors mechanisms are not yet fully understood remain frequent research topic. For this reason, narrative review concentrates issue potential cause OSCC, well underlying involved.

Language: Английский

Citations

6
Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer DOI Creative Commons

Ryunosuke Hoshi,

Kristyna A. Gorospe,

Hagar I. Labouta

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(9), P. 1181 - 1181

Published: Sept. 7, 2024

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster differentiation 8 (CD8)+ T cell-mediated responses. Engagement PD-L1 with PD-1 expressed on CD8+ cells activates downstream signaling pathways that culminate in cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer exploit this by overexpressing facilitate escape. Intravenously (IV) administered inhibitors (ICIs) block the interaction between PD-1/PD-L1 have achieved great success reversing and promoting tumor regression various malignancies. However, ICIs can cause immune-related adverse events (irAEs) due off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies enhance tumor-directed reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted immunotherapy associated We then provide a detailed review approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, ultrasound microbubble (USMB)-mediated are currently under investigation enhancing tumor-specific minimize toxic effects. conclude commentary key challenges methods potential mitigate them.

Language: Английский

Citations

4