Anti-TGF-β/PD-L1 bispecific antibody synergizes with radiotherapy to enhance antitumor immunity and mitigate radiation-induced pulmonary fibrosis

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: March 5, 2025

Despite the success of immune checkpoint inhibitors (ICIs) in multiple malignant tumors, a significant proportion patients remain unresponsive to treatment. Radiotherapy (RT) elicits immunogenic antitumor responses but concurrently activates several evasion mechanisms. Our earlier research demonstrated efficacy YM101, an anti-TGF-β/PD-L1 bispecific antibody, stroma-rich tumors. Nevertheless, YM101 has reduced effectiveness non-inflamed tumors characterized by poor cell infiltration. This study investigated potential synergy between RT and overcoming immunotherapy resistance mitigating RT-induced pulmonary fibrosis. The activity survival outcomes plus treatment vivo were explored murine tumor models. Furthermore, inhibition metastases was assessed metastasis model. impact on dendritic (DC) maturation quantified flow cytometry, whereas cytokine chemokine secretions measured ELISA. To comprehensively characterize changes microenvironment, we utilized combination methods, including IHC staining, multiplex inmunofluorecence RNA sequencing. Additionally, evaluated significantly inhibited growth, prolonged compared with monotherapies promoted DC dose-dependent manner increased proinflammatory cytokines. Mechanistically, simultaneously infiltration activation intratumoral DCs tumor-infiltrating lymphocytes reshaped microenvironment landscape. Notably, attenuated both peritumoral fibrosis findings suggest that combined enhances immunity overcomes preclinical models, while showing therapy demonstrates promise ICI resistance, potentially sparing normal tissue, thereby providing strong rationale for further clinical investigations.

Language: Английский

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Recent Treatment Strategies and Molecular Pathways in Resistance Mechanisms of Antiangiogenic Therapies in Glioblastoma

Cancers, Journal Year: 2024, Volume and Issue: 16(17), P. 2975 - 2975

Published: Aug. 27, 2024

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing formation new vasculature (antiangiogenic treatments) or destroying formed tumor (vascular disrupting agents) show promise. This study summarizes existing knowledge regarding processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses activation redundant proangiogenic pathways, heightened cell invasion metastasis, induced hypoxia, creation vascular mimicry channels, regulation immune microenvironment. Subsequently, we explore potential strategies overcome this resistance, such as combining other methods, personalizing treatments for each patient, focusing on therapeutic targets, incorporating immunotherapy, utilizing drug delivery systems based nanoparticles. Additionally, would like discuss limitations methods future directions enhance beneficial effects patients GBM. Therefore, review aims research outcome GBM provide a more promising opportunity thoroughly exploring mechanisms investigating novel strategies.

Language: Английский

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Next-Generation Immunotherapy for Hepatocellular Carcinoma: Mechanisms of Resistance and Novel Treatment Approaches

Cancers, Journal Year: 2025, Volume and Issue: 17(2), P. 236 - 236

Published: Jan. 13, 2025

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and, with only 15-20% HCC patients being suitable for potentially curative treatments, the vast majority ultimately require systemic therapy. For decades, choice effective therapy remained sparse. In recent years, after combination atezolizumab and bevacizumab demonstrated superior overall survival over first-line standard, sorafenib, there has been major therapeutic paradigm shift to immunotherapy-based regimens HCC. While representing great leap forward treatment this cancer, reality that less than one-third achieve an objective response immune checkpoint inhibitor-based therapy, so remains significant clinical need further optimization. review, we provide overview current landscape immunotherapy unresectable delve into tumor intrinsic extrinsic mechanisms resistance established immunotherapies focus on novel targets strong translational potential. Following this, spotlight emerging approaches notable trials aiming optimize efficacy in include inhibitors, microenvironment modulators, targeted delivery systems, locoregional interventions.

Language: Английский

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Hepatocellular Carcinoma Immunotherapy: Predictors of Response, Issues, and Challenges

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(20), P. 11091 - 11091

Published: Oct. 15, 2024

Immune checkpoint inhibitors (ICIs), such as durvalumab, tremelimumab, and atezolizumab, have emerged a significant therapeutic option for the treatment of hepatocellular carcinoma (HCC). In fact, efficacy ICIs single agents or part combination therapies has been demonstrated in practice-changing phase III clinical trials. However, confront several difficulties, including lack predictive biomarkers, primary secondary drug resistance, treatment-related side effects. Herein, we provide an overview current issues future challenges this setting.

Language: Английский

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A KIF20A-based thermosensitive hydrogel vaccine effectively potentiates immune checkpoint blockade therapy for hepatocellular carcinoma

npj Vaccines, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 3, 2025

Language: Английский

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LARP3 inhibits the apoptosis of hepatocellular carcinoma via the ROS/PI3K/c-Fos axis

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(1), P. e0317454 - e0317454

Published: Jan. 17, 2025

Primary hepatocellular carcinoma (PHC) is the sixth most common cancer and third leading cause of death worldwide. Hepatocellular (HCC) accounts for 75%-85% PHC. LARP3 aberrantly expressed in multiple cancers. We found that it significantly highly liver tissues HCC patients, but exact role specific mechanism this abnormal expression are not yet clear. In study, through bioinformatics analysis, we concluded associated with a poor prognosis patients HCC. Through cellular experiments such as gene editing phenotypic functions, promotes occurrence development inhibits apoptosis. Finally, biological means RNA sequencing, flow cytometry, western blotting, construction subcutaneous tumorigenesis model nude mice, inhibition apoptosis by related to negatively regulating ROS level inhibiting PI3K/c-Fos/apoptosis axis. This study will provide potential targets treatment

Language: Английский

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Structural insights into antibody-based immunotherapy for hepatocellular carcinoma

Genomics & Informatics, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 20, 2025

Abstract Hepatocellular carcinoma (HCC) is one of the most common types primary liver cancer and remains a leading cause cancer-related deaths worldwide. While traditional approaches like surgical resection tyrosine kinase inhibitors struggle against tumor’s immune evasion, monoclonal antibody (mAb)-based immunotherapies have emerged as promising alternatives. Several therapeutic antibodies that counter immunosuppressive tumor microenvironment demonstrated efficacy in clinical trials, to FDA approvals for advanced HCC treatment. A crucial aspect advancing these therapies lies understanding structural interactions between their targets. Recent findings indicate mAbs bispecific (bsAbs) can target different, non-overlapping epitopes on checkpoints such PD-1 CTLA-4. This review delves into epitope-paratope structurally unresolved bsAbs, discusses potential combination based epitopes. By leveraging this unique feature, could enhance activation, reduce resistance, improve overall efficacy, marking new direction antibody-based immunotherapy HCC.

Language: Английский

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Application of multi-omics in hepatocellular carcinoma: new prospects for classification and precise diagnosis and treatment

Hepatoma Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Hepatocellular carcinoma (HCC) represents a significant global health challenge, with complex etiology and limited treatment options. The integration of multi-omics technologies, including genomics, transcriptomics, proteomics, metabolomics, has revolutionized our understanding HCC, offering novel insights into its molecular underpinnings. This comprehensive review synthesizes the current knowledge on application in highlighting role disease classification, early detection, development targeted therapies. We discuss identification key driver mutations single nucleotide polymorphisms (SNPs) that enhance risk prediction models, implications for personalized medicine. approach facilitated discovery distinct HCC subtypes, each unique signatures tumor microenvironments (TME), which are critical predicting prognosis guiding strategies. Furthermore, we explore these findings precision medicine, emphasizing potential biomarker therapies, immune checkpoint blockade (ICB). concludes by underscoring transformative impact research clinical practice, heralding new era medicine promise improved patient outcomes.

Language: Английский

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The cyclin‐dependent kinase inhibitor AT7519 is a human RORγt agonist

Immunology and Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Abstract AT7519, which inhibits multiple cyclin‐dependent kinases, has been extensively investigated in various types of cancer cells. Previous studies have demonstrated the ability this molecule to suppress expression nuclear receptor retinoic acid–related orphan gamma (RORγ) and several genes involved hepatocellular carcinoma progression. In study, we identified a distinct agonistic effect AT7519 on RORγt, an isoform expressed by immune cells, including T helper 17 lymphocytes. These cells play pivotal roles shaping tumor microenvironment promoting anticancer response system. After exposure during differentiation, primary human CD4 + presented increased IL17A/F , IFNG GZMB decreased PDCD1 CTLA4 . findings elucidate previously unrecognized facet activity suggest potential incorporation into therapies augment effectiveness diverse strategies involving anti–programmed cell death protein 1 (anti–PD‐1) anti–cytotoxic T‐lymphocyte antigen 4 (anti– ) regimens.

Language: Английский

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Role of liposomes in chemoimmunotherapy of Breast cancer

Journal of drug targeting, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 43

Published: Feb. 19, 2025

In the dynamic arena of cancer therapeutics, chemoimmunotherapy has shown tremendous promise, especially for aggressive forms breast like triple-negative (TNBC). This review delves into significant role liposomes in enhancing effectiveness by leveraging cancer-specific mechanisms such as induction immunogenic cell death (ICD), reprogramming tumor microenvironment (TME), and enabling sequential drug release. We examine innovative dual-targeting that capitalize on heterogeneity, well pH-sensitive formulations offer improved control over delivery. Unlike prior analyses, this directly links advancements preclinical research-such PAMAM dendrimer-based nanoplatforms RGD-decorated liposomes-to clinical trial results, highlighting their potential to revolutionize TNBC treatment strategies. Additionally, we address ongoing challenges related scalability, toxicity, regulatory compliance, propose future directions personalized, immune-focused nanomedicine. work not only synthesizes latest research but also offers a framework translating liposomal from laboratory practice.

Language: Английский

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