ImmunoTargets and Therapy最新文献

{"title":"Comparative Effectiveness and Safety of Molecular Targeted Therapy Plus PD-(L)1 with or without TACE in Unresectable Hepatocellular Carcinoma: A Retrospective Study.","authors":"Jiangtao Liu, Yan Wang, Li Cui, Yan Nie, Chao Li, Wenle Tan, Ye Li, Yanhua Bai, Tao Wan, Bingyang Hu, Zhe Liu, Minggen Hu, Maoqiang Wang, Feng Duan","doi":"10.2147/ITT.S495451","DOIUrl":"10.2147/ITT.S495451","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to compare the effectiveness and safety of TACE combined with molecular targeted therapy (MTT) plus Programmed death-ligand 1 (PD-(L)1) antibodies versus MTT plus PD-(L)1 antibodies for HCC patients.</p><p><strong>Methods: </strong>Data from HCC patients who received either MTT plus PD-(L)1 (systemic therapy group) or TACE combined with MTT plus PD-(L)1 (combination therapy group) were retrospectively analyzed. The primary outcome was the objective reaction rate (ORR) at the initial assessment post-treatment initiation. Secondary outcomes included progressive free survival (PFS), overall survival (OS) and grade-3 or higher adverse events.</p><p><strong>Results: </strong>A total of 222 HCC patients were included (109 in the systemic therapy group, 113 in the combination therapy group). Propensity score matching yielded 80 patients per group. The odds ratio for ORR in the combination therapy group was 1.29 (95% CI: 0.64-2.60; p=0.479). Subgroup analysis revealed significantly higher ORR for patients with AFP≤200 ng/mL in the combination therapy group (OR=3.54, p=0.016). For patients without PVTT, the ORR odds were slightly higher with combination therapy (OR=5.33, p=0.068). Multivariate Cox regression analysis showed no significant differences in PFS (HR=0.68, p=0.131) or OS (HR=0.86, p=0.674) between the two groups. Higher baseline AFP (>200 ng/mL) was associated with worse PFS (HR=1.68, p=0.012) and OS (HR=2.33, p=0.021). Surgical resection improved PFS (HR=0.42, p<0.001) and OS (HR=0.31, p=0.004). Grade 3 or higher adverse events were more common in the combination therapy group (52% vs 15%, p<0.0001).</p><p><strong>Conclusion: </strong>No significant benefits were observed for combining TACE with MTT and PD-(L)1 in unresectable HCC patients. However, TACE may offer advantages for patients with AFP≤200 ng/mL or without PVTT.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"761-771"},"PeriodicalIF":6.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of Radioligand Therapy and Immunotherapy: How to Make It Work in Clinic?","authors":"Rubin Jiao, Ekaterina Dadachova","doi":"10.2147/ITT.S485643","DOIUrl":"10.2147/ITT.S485643","url":null,"abstract":"<p><p>Combining external beam radiation therapy (EBRT) with immunotherapy showed promise pre-clinically by inducing immunogenic cell death (ICD) thus releasing damage-associated molecular patterns (DAMPs) and cytokines to activate the immune system. Clinical results, however, have often been disappointing. Radioligand therapy (RL), which uses targeted radionuclides to deliver cytotoxic radiation, offers advantages over EBRT by treating multiple tumors simultaneously. Combining RL with immunotherapy faces challenges, as prolonged radiation exposure can damage immune cells, and the \"cross-fire\" and \"bystander\" effects may harm incoming effector cells. Current RL therapies require multiple doses, further complicating immune cell viability. To optimize RL-immunotherapy combinations, timing is critical. Administering immunotherapy weeks after RL therapy may reduce radiation-induced immune cell damage. Additionally, selecting radionuclides with shorter half-lives could minimize immune cell toxicity while maintaining tumor-killing efficacy. Future RL therapies should prioritize radionuclides with optimal emission profiles and half-lives to enhance synergy with immunotherapy and improve clinical outcomes.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"755-759"},"PeriodicalIF":6.2,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune Microenvironment on the Molecular Mechanisms and Therapeutic Targets of MAFLD.","authors":"Zhonghao Jiang, Baolin Qian, Tongjie Xu, Junjie Bai, Wenguang Fu","doi":"10.2147/ITT.S530451","DOIUrl":"10.2147/ITT.S530451","url":null,"abstract":"<p><p>Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most prevalent chronic liver diseases worldwide. It is characterized by hepatic steatosis in the absence of significant alcohol consumption, and can progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Despite its widespread impact, treatment options remain limited, and effective therapies targeting the underlying disease mechanisms are lacking. Recent studies have highlighted the critical role of the liver's immune microenvironment in the onset and progression of MAFLD. However, research into immune-based therapies remains in its early stages. Most existing studies have focused on understanding the immune mechanisms involved, but specific immune targets and therapeutic strategies have yet to be fully explored. This gap has hindered the development of targeted immunotherapies for MAFLD. This review aims to examine the molecular mechanisms of the immune microenvironment in MAFLD and identify potential therapeutic targets, offering insights for future clinical and scientific advancements.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"719-733"},"PeriodicalIF":6.2,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation of a B7-H3 Targeting Antibody Enhancing NK Cell-Mediated Cytotoxicity for Ovarian Cancer Treatment.","authors":"Ilona Hagelstein, Sven Mattern, Kevin Wang, Yannick E Haueisen, Sarah M Greiner, Alexander Englisch, Annette Staebler, Stephan Singer, Martina S Lutz","doi":"10.2147/ITT.S521008","DOIUrl":"10.2147/ITT.S521008","url":null,"abstract":"<p><strong>Background: </strong>Despite the advancements in treatment, ovarian cancer remains the deadliest gynecological malignancy. The dismal prognosis of the disease necessitates the urgent development of novel therapies. Monoclonal antibodies (mAbs) have transformed cancer treatment, yet their effectiveness in ovarian cancer remains limited. A key mechanism in mAb therapy is antibody-dependent cellular cytotoxicity (ADCC), driven by natural killer (NK) cells targeting tumor cells. Optimization of the Fc domain of mAbs to enhance efficacy has therefore become a subject of extensive research. The costimulatory molecule B7-H3 is overexpressed in various cancers, including ovarian cancer, making it a promising target for anti-tumor mAb immunotherapy. This study evaluates the preclinical potential of an Fc-optimized B7-H3-targeting antibody for ovarian cancer treatment.</p><p><strong>Methods: </strong>The expression of B7-H3 was evaluated in tumor samples from 43 ovarian cancer patients using immunohistochemistry. A chimeric B7-H3 mAb was developed with a wildtype Fc (8H8-WT) and an Fc-optimized variant (8H8-SDIE) containing S239D/I332E substitutions to enhance CD16 binding and subsequent activation of NK cells. The therapeutic effects of 8H8-SDIE were evaluated through NK cell activation, cytokine release, and cytotoxicity assays.</p><p><strong>Results: </strong>A total of 43 ovarian cancer samples were analyzed, and it was found that all of them expressed B7-H3. In addition, 8H8-SDIE was found to demonstrate significantly higher affinity for CD16 than 8H8-WT, with minimal effects on other Fc receptors. Functional assays confirmed that 8H8-SDIE enhanced NK cell activation and promoted IFN-γ and TNF release. Furthermore, 8H8-SDIE induced robust cytotoxicity against B7-H3-expressing ovarian cancer cells in both short-term and long-term assays.</p><p><strong>Conclusion: </strong>8H8-SDIE has been shown to induce potent NK cell activity, resulting in tumor cell lysis. This finding underscores its promise as an innovative immunotherapeutic approach for the treatment of ovarian cancer.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"735-753"},"PeriodicalIF":6.2,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Aspartate β-Hydroxylase Enhances Anti-Tumor Immunity.","authors":"Shweta Dilip Johari, Katerina Krausova, Barbora Zucha, Carlos Eduardo Madureira Trufen, Ingrid Polakova, Mark Olsen, Michal Smahel","doi":"10.2147/ITT.S530987","DOIUrl":"10.2147/ITT.S530987","url":null,"abstract":"<p><strong>Purpose: </strong>Aspartate β-hydroxylase (ASPH) contributes to carcinogenesis by promoting tumor cell proliferation, migration, and invasion. The enzymatic activity of ASPH can be inhibited by small molecule inhibitors that have been shown to have anti-metastatic activity in rodent models. ASPH has also been shown to inhibit the activation of natural killer (NK) cells. Therefore, this study aimed to investigate the effect of ASPH inhibition on the induction of anti-tumor immunity and to analyze the immune cells involved.</p><p><strong>Methods: </strong>In the mouse TC-1/A9 model characterized by reversible downregulation of major histocompatibility class I (MHC-I) molecules, ASPH inhibition was combined with stimulation of innate and/or adaptive immunity, and the anti-tumor response was analyzed by evaluation of tumor growth, in vivo depletion of immune cell subpopulations, and ELISPOT assay. Characteristics of immune cells in the spleen and tumor were determined by flow cytometry and single-cell RNA sequencing (scRNA-seq).</p><p><strong>Results: </strong>ASPH inhibition did not reduce tumor growth or promote the anti-tumor effect of innate immunity stimulation with the synthetic oligonucleotide ODN1826, but it significantly enhanced tumor growth reduction induced by DNA vaccination. In vivo immune cell depletion suggested that CD8⁺ T cells played a critical role in this immunity stimulated by combined treatment with ASPH inhibition and DNA vaccination. ASPH inhibition also significantly enhanced the specific response of CD8⁺ T cells induced by DNA vaccination in splenocytes, as detected by ELISPOT assay, and reduced the number of regulatory T cells in tumors. scRNA-seq confirmed the improved activation of CD8⁺ T cells in tumor-infiltrating cells after combined therapy with DNA vaccination and ASPH inhibition. It also showed activation of NK cells, macrophages, and dendritic cells in tumors.</p><p><strong>Conclusion: </strong>ASPH inhibition stimulated T-cell-mediated adaptive immunity induced by DNA vaccination. Different types of lymphoid and myeloid cells were likely involved in the activated immune response that was efficient against tumors with MHC-I downregulation, which are often resistant to T-cell-based therapies. Due to different types of activated immune cells, ASPH inhibition could improve immunotherapy for tumors with various MHC-I expression levels.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"697-718"},"PeriodicalIF":6.2,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-6 Signaling in Immunopathology: From Basic Biology to Selective Therapeutic Intervention.","authors":"Tim Schumertl, Juliane Lokau, Christoph Garbers","doi":"10.2147/ITT.S485684","DOIUrl":"10.2147/ITT.S485684","url":null,"abstract":"<p><p>Interleukin-6 (IL-6) is a cytokine with pro- and anti-inflammatory functions. Interestingly, its divergent biological activities are mediated by different signaling pathways: In IL-6 classic signaling, which is associated with the regenerative and anti-inflammatory properties of the cytokine, IL-6 binds to and signals via the membrane-bound IL-6 receptor (IL-6R) on its target cells. In contrast, the pro-inflammatory properties of IL-6 are mediated via the soluble (s)IL-6R (IL-6 trans-signaling). Recently, a third mode of IL-6 signaling was revealed, which was termed cluster signaling and is required for the generation of pathogenic Th17 cells. In all pathways, intracellular signaling cascades are activated via the formation of a gp130 homodimer. The involvement of IL-6 in the pathogenesis of inflammatory diseases, autoimmune diseases and even cancer has made IL-6 and the IL-6R important therapeutic targets. Consequently, antibodies that block either IL-6 itself or the IL-6R are in clinical use and have been approved for different inflammatory diseases, including rheumatoid arthritis (RA). This review gives an overview about the complex biology of this important cytokine, summarizes the current usage of anti-IL-6 therapeutics in clinical use and highlights the pre-clinical and clinical development of novel therapeutic agents that specifically block only the trans-signaling pathway of IL-6.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"681-695"},"PeriodicalIF":6.2,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current Advances and Challenges in CAR-T Therapy for Hematological and Solid Tumors.","authors":"Gengtian Zhang, Mengyao Bai, Hanzhi Du, Yue Yuan, Yidan Wang, Weijing Fan, Huachao Zhu, Di Wu, Pengcheng He, Busheng Xue","doi":"10.2147/ITT.S519616","DOIUrl":"10.2147/ITT.S519616","url":null,"abstract":"<p><strong>Introduction: </strong>Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of refractory hematological malignancies, yet significant challenges persist in extending its success to solid tumors. This review aims to provide a comprehensive overview of the current landscape and future perspectives of CAR-T therapy in both hematological malignancies and solid tumors.</p><p><strong>Methods: </strong>A thorough literature search was conducted to identify relevant preclinical and clinical studies, as well as review articles, focusing on CAR-T therapy in various hematological malignancies and solid tumors. The collected information was synthesized to discuss the current applications, challenges, and strategies for improving CAR-T therapy in these settings.</p><p><strong>Results: </strong>CAR-T therapy has demonstrated impressive clinical outcomes in treating certain hematological malignancies, such as B-cell lymphoma, leukemia, and multiple myeloma. However, the efficacy of CAR-T cells in solid tumors has been limited due to various obstacles, including tumor heterogeneity, immunosuppressive microenvironment, and off-tumor toxicities. Strategies to overcome these challenges involve advanced CAR designs, combination therapies, and novel approaches to CAR-T cell manufacturing and engineering.</p><p><strong>Conclusion: </strong>While CAR-T therapy has revolutionized the treatment of some hematological malignancies, significant hurdles remain in extending its success to solid tumors. Continued research efforts focusing on improving CAR-T cell efficacy, safety, and accessibility will be crucial in unlocking the full potential of this innovative immunotherapeutic approach across a broad spectrum of cancer types.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"655-680"},"PeriodicalIF":6.2,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12212355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing Adjuvant Immunotherapy in Hepatocellular Carcinoma: A Comprehensive Review.","authors":"Miho Akabane, Odysseas P Chatzipanagiotou, Yuki Imaoka, Austin Schenk, Timothy M Pawlik","doi":"10.2147/ITT.S528709","DOIUrl":"10.2147/ITT.S528709","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with high rates of recurrence even after curative-intent treatments such as hepatectomy and liver transplantation (LT). In recent years, immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for HCC, demonstrating significant efficacy among advanced-stage tumors through combination regimens, such as anti-programmed cell death ligand-1 (PD-L1)/PD-1 inhibitors with anti-vascular endothelial growth factor agents. Recent advances have highlighted the potential of ICIs as adjuvant therapy to improve recurrence-free survival among high-risk patients post-resection. However, challenges such as low immunogenicity, the immunosuppressive tumor microenvironment, and immune resistance remain substantial barriers to the broader success of ICIs. In the context of LT, the use of ICIs is further complicated by the concurrent need for immunosuppressive agents, which can exacerbate the risk of recurrence. Emerging strategies focusing on the optimization of the timing of ICI therapy and the utilization of novel biomarkers are being explored to mitigate graft rejection while maintaining antitumor efficacy. Additionally, immune-cell-based therapies based on chimeric antigen receptor-T and natural killer (NK) cells, adoptive cell transfer, and liver-resident NK cell approaches are also being investigated for their potential to reduce recurrence and improve survival outcomes. This review focuses on the current landscape of adjuvant immunotherapy and immune-cell therapy in the postoperative management of HCC, highlighting ongoing clinical trials, therapeutic potential, and associated risks. With continued advancements in immunotherapeutic strategies and personalized approaches, these therapies hold the promise of transforming outcomes for patients undergoing curative resection or LT.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"631-654"},"PeriodicalIF":6.2,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotargets and Therapy for Systemic Lupus Erythematosus.","authors":"Chi Chiu Mok","doi":"10.2147/ITT.S485650","DOIUrl":"10.2147/ITT.S485650","url":null,"abstract":"<p><p>The pathophysiology of systemic lupus erythematosus (SLE) is complex and involves most cell types of the innate and adaptive immune system. Impaired clearance of apoptotic bodies and self-antigens, dysregulated cytokine network and aberrated functions of the immune cells lead to overproduction of autoantibodies, activation of complements, immune complex deposition and tissue injury. Novel biological and newer generation immunosuppressive agents have been developed to target the B cells, T cells, T/B cell interaction, plasmacytoid dendritic cells and the cytokines. With the advances in the knowledge about the intracellular pathways, small molecules that inhibit the downstream signal transduction from surface receptors and intracellular protein degradation by the ubiquitin-proteasome system are being developed in the pipeline. This article summarizes the evidence of various immunotargets for the treatment of SLE. These novel agents target specific cellular mechanisms, and further works are necessary to stratify patients according to biomarkers to receive individualized therapies that could help maximize the clinical response. With the availability of more therapeutic choices, a combination approach to achieve synergistic effects while reducing adverse events by dosage reduction of individual drugs is being explored for SLE patients at risk of disease progression or refractory to conventional therapies.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"605-629"},"PeriodicalIF":6.2,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-β Decreases NK Cell Mobility and Cytotoxic Efficacy in Complex in vitro Models of the Leukemia Microenvironment.","authors":"Veronika Švubová, Lucie Janstová, Marek Jedlička, Eva Mašínová, Jana Szabová, Tereza Feglarová, Kateřina Kuglerová, Veronika Bosáková, Barbora Brodská, Kristýna Boráková, David Kundrát, Iva Trsová, Martina Böhmová, Kateřina Kuželová, Jiří Hrdý, Zdenka Gašová, Jan Vydra, Michaela Dostálová Merkerová, Marcela Hortová-Kohoutková, Jan Frič","doi":"10.2147/ITT.S512700","DOIUrl":"10.2147/ITT.S512700","url":null,"abstract":"<p><strong>Background: </strong>Natural killer (NK) cell-based therapies represent a promising approach for acute myeloid leukemia (AML) relapse, yet their efficacy is hindered by immunosuppressive factors such as transforming growth factor beta (TGF-β) in the tumor microenvironment. This study investigated the effects of TGF-β on NK cell cytotoxicity and migration using 2D and 3D co-culture models that mimic the leukemic microenvironment.</p><p><strong>Methods: </strong>TGF-β production was evaluated in AML-derived leukemic cell lines and mesenchymal stromal cells (hTERT-MSCs) using ELISA. Bulk RNA sequencing (RNA-seq) was performed to analyze global gene expression changes in TGF-β-treated primary human NK cells. NK cell cytotoxicity and migration were assessed in 2D monolayer and 3D spheroid co-cultures containing hTERT-MSCs and leukemic cells using flow cytometry and confocal microscopy.</p><p><strong>Results: </strong>Both leukemic cells and MSCs produced TGF-β, with increased levels observed in MSCs after co-culture with primary AML blasts. RNA sequencing revealed that TGF-β altered key gene pathways associated with NK cell cytotoxicity, adhesion, and migration, supporting its immunosuppressive role. In functional assays, TGF-β exposure significantly reduced NK cell-mediated cytotoxicity in a time-dependent manner and impaired NK cell infiltration into 3D spheroids, particularly in models incorporating MSCs. Additionally, MSCs themselves provided a protective environment for leukemic cells, further reducing NK cell effectiveness in 2D co-cultures.</p><p><strong>Conclusion: </strong>TGF-β suppresses both NK cell cytotoxicity and migration, limiting their ability to eliminate leukemic cells and infiltrate the bone marrow niche (BMN). These findings provide novel insights into TGF-β-mediated immune evasion mechanisms and provide important insights for the future design of NK-based immunotherapies and clinical trials.</p>","PeriodicalId":30986,"journal":{"name":"ImmunoTargets and Therapy","volume":"14 ","pages":"589-604"},"PeriodicalIF":6.2,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}