Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 7, 2025

Abstract Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as promising therapeutic approach. However, significant proportion patients exhibit primary or acquired resistance, limiting the overall efficacy immunotherapy. This review provides comprehensive analysis mechanisms underlying immunotherapy resistance GC, including role tumor microenvironment, dynamic PD-L1 expression, compensatory activation other checkpoints, and genomic instability. Furthermore, explores GC-specific factors such molecular subtypes, unique evasion mechanisms, impact Helicobacter pylori infection. We also discuss emerging strategies to overcome combination therapies, novel immunotherapeutic approaches, personalized based on genomics microenvironment. By highlighting these key areas, this aims inform future research directions clinical practice, ultimately improving outcomes for GC undergoing

Язык: Английский

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OLFM4 promotes the progression of intestinal metaplasia through activation of the MYH9/GSK3β/β-catenin pathway

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Июнь 7, 2024

Abstract Background Intestinal metaplasia (IM) is classified into complete intestinal (CIM) and incomplete (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring critical need for early screening measures. In addition complexities associated diagnosis, exact mechanisms driving progression cancer in patients remain poorly understood. OLFM4 overexpressed several types tumors, including colorectal, gastric, pancreatic, ovarian cancers, its expression has been tumor progression. Methods this study, we used pathological sections from two clinical centers, biopsies IM tissues, precancerous lesions (PLGC) cell models, animal organoids explore role IIM. Results Our results show that highly increased IIM, superior diagnostic accuracy when compared CDX2 MUC2. OLFM4, along MYH9, was PLGC models. Furthermore, combination Myosin heavy chain 9 (MYH9), accelerated ubiquitination GSK3β resulted β-catenin levels through Wnt signaling pathway, promoting proliferation invasion abilities cells. Conclusions represents a novel biomarker could be utilized as important auxiliary means delimit key population screening. Finally, our study identifies pathways involved IM.

Язык: Английский

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Research progress on the immune microenvironment and immunotherapy in gastric cancer

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Ноя. 23, 2023

The tumor microenvironment, particularly the immune plays an indispensable role in malignant progression and metastasis of gastric cancer (GC). As our understanding GC microenvironment continues to evolve, we are gaining deeper insights into biological mechanisms at single-cell level. This, turn, has offered fresh perspectives on therapy. Encouragingly, there various monotherapy combination therapies use, such as checkpoint inhibitors, adoptive cell transfer therapy, chimeric antigen receptor T antibody-drug conjugates, vaccines. In this paper, review current research progress regarding summarize promising immunotherapy targeted therapies.

Язык: Английский

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Tumor Microenvironment: Nurturing Cancer Cells for Immunoevasion and Druggable Vulnerabilities for Cancer Immunotherapy

Cancer Letters, Год журнала: 2024, Номер 611, С. 217385 - 217385

Опубликована: Дек. 6, 2024

Язык: Английский

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Liver Metastasis in Cancer: Molecular Mechanisms and Management

MedComm, Год журнала: 2025, Номер 6(3)

Опубликована: Фев. 27, 2025

Abstract Liver metastasis is a leading cause of mortality from malignant tumors and significantly impairs the efficacy therapeutic interventions. In recent years, both preclinical clinical research have made significant progress in understanding molecular mechanisms strategies liver metastasis. Metastatic tumor cells different primary sites undergo highly similar biological processes, ultimately achieving ectopic colonization growth liver. this review, we begin by introducing inherent metastatic‐friendly features We then explore panorama conclude three continuous, yet distinct phases based on liver's response to This includes metastatic sensing stage, stress support stage. discuss intricate interactions between various resident recruited cells. addition, emphasize critical role spatial remodeling immune Finally, review advancements challenges faced management Future precise antimetastatic treatments should fully consider individual heterogeneity implement targeted interventions stages

Язык: Английский

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Sp1 mechanotransduction regulates breast cancer cell invasion in response to multiple tumor-mimicking extracellular matrix cues

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 19, 2025

Abstract Breast cancer progression is marked by extracellular matrix (ECM) remodeling, including increased stiffness, faster stress relaxation, and elevated collagen levels. In vitro experiments have revealed a role for each of these factors to individually promote malignant behavior, but their combined effects remain unclear. To address this, we developed alginate-collagen hydrogels with independently tunable density. We show that tumor-mimicking ECM cues reinforced invasive morphologies promoted spheroid invasion in breast mammary epithelial cells. High stiffness low density slow-relaxing matrices led the greatest cell migration speed displacement. RNA-seq Sp1 target gene enrichment response both individual cues, greater observed under multiple cues. Notably, high expression genes upregulated fast relaxation correlated poor patient survival. Mechanistically, found phosphorylated-Sp1 (T453) was increasingly located nucleus stiff and/or relaxing matrices, which regulated PI3K ERK1/2 signaling, as well actomyosin contractility. This study emphasizes how complex microenvironments reinforce traits supports an emerging mechanoresponsive transcription factor.

Язык: Английский

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Potential target within the tumor microenvironment - MT1-MMP

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Март 24, 2025

Matrix metalloproteinases are integral to the modification of tumor microenvironment and facilitate progression by degrading extracellular matrix, releasing cytokines, influencing recruitment immune cells. Among matrix metalloproteinases, membrane-type metalloproteinase 1 (MT1-MMP/MMP14) is first identified MMP acts as an essential proteolytic enzyme that enables infiltration metastatic progression. Given pivotal role MT1-MMP in correlation between its overexpression tumors unfavorable prognoses across multiple cancer types, a comprehensive understanding potential functional mechanisms essential. This knowledge will aid advancement diverse anti-tumor therapies aimed at targeting MT1-MMP. Although contemporary research has highlighted considerable targeted therapy, studies pertaining application cell therapy remain relatively limited. In this review, we delineate structural characteristics regulatory expression, well biological significance tumorigenesis. Finally, discussed current status prospects

Язык: Английский

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New approaches of chimeric antigen receptor (CAR)-immune cell-based therapy in gastric cancer; highlight CAR-T and CAR-NK

Functional & Integrative Genomics, Год журнала: 2025, Номер 25(1)

Опубликована: Март 25, 2025

Язык: Английский

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Dynamic evolution of NK cells and immune remodeling mediated by CRS+HIPEC: prognostic mechanisms and therapeutic implications for malignant peritoneal mesothelioma

Опубликована: Апрель 21, 2025

Background: Malignant peritoneal mesothelioma (MPM) is a highly aggressive malignancy with significant recurrence rate following cytoreductive surgery (CRS) combined hyperthermic intraperitoneal chemotherapy (HIPEC). Thus, there an urgent need to investigate novel therapeutic strategies for MPM. Natural killer (NK) cells exhibit rapid responsiveness in anti-tumor immunity; however, NK cells' dynamic evolution and clinical significance MPM remain unclear. Methods: This study retrospectively enrolled 80 newly diagnosed patients (preoperative group) 64 who underwent CRS+HIPEC (postoperative group). The frequency of (CD3^-CD56^dimCD16⁺) peripheral blood was quantified using flow cytometry. Univariate multivariate regression analyses were performed evaluate the association between cell counts clinicopathological characteristics, intraoperative events, prognosis. A prediction model recovery established. Results: Preoperative reduction observed 41 (51.3%), this phenomenon significantly associated preoperative thrombosis (P = 0.023), high plasma infusion volume 0.004), prolonged hospital stay decreased total lymphocyte count 0.011), elevated CD4⁺/CD8⁺T ratio 0.018). median increased 278 cells/μL postoperatively. Postoperative occurred 20 cases (31.3%), which independently correlated lower Karnofsky performance scale (KPS) scores 0.048), higher expression levels interleukins IL-4 0.020), IL-5 0.007), IL-6 0.016), IL-8 Elevated IL-2 0.019) 0.007) identified as independent factors contributing depletion surgery. Survival analysis revealed that perioperative stress score (PSS) 0.015), lymph node metastasis loss 0.013), low CD8⁺T 0.001), postoperative IL-17 0.013) adverse predictors overall survival (OS). Patients exhibited tendency toward longer OS. Furthermore, demonstrated baseline < cancer index (PCI) status time 0.001) all influenced immune remodeling process. Conclusions: represents first systematic investigation into spatiotemporal characteristics patients. More than half experienced depletion, could effectively reverse. may serve biomarker tumor burden immunosuppressive microenvironment assessment, its elevation potentially improving Targeting IL-2/IL-4 pathway alone or combination CD8⁺ T offer strategy immunotherapy.

Язык: Английский

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Role of post-translational modifications of Sp1 in cancer: state of the art

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Авг. 20, 2024

Specific protein 1 (Sp1) is central to regulating transcription factor activity and cell signaling pathways. Sp1 highly associated with the poor prognosis of various cancers; it considered a non-oncogene addiction gene. The function complex contributes extensive transcriptional activity, apart from maintaining basal transcription. stability are affected by post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, glycosylation, SUMOylation. These help determine genetic programs that alter structure in different cells increase or decrease its DNA binding response pathophysiological stimuli. Investigating PTMs will contribute deeper understanding mechanism underlying pathway regulatory which affects cancer progression. Furthermore, facilitate development new drug targets biomarkers, thereby elucidating considerable implications prevention treatment cancer.

Язык: Английский

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