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

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 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

Language: Английский

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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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Immune Watchdogs: Tissue-Resident Lymphocytes as Key Players in Cancer Defense

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: 208, P. 104644 - 104644

Published: Feb. 1, 2025

Language: Английский

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Optogenetically Activatable MLKL as a Standalone Functional Module for Necroptosis and Therapeutic Applications in Antitumoral Immunity

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Necroptosis plays a crucial role in the progression of various diseases and has gained substantial attention for its potential to activate antitumor immunity. However, complex signaling networks that regulate necroptosis have made it challenging fully understand mechanisms translate this knowledge into therapeutic applications. To address these challenges, an optogenetically activatable system is developed allows precise spatiotemporal control key regulators, bypassing upstream processes. The system, specifically featuring optoMLKL, demonstrates can rapidly assemble functional higher-order "hotspots" within cellular membrane compartments, independent RIPK3-mediated phosphorylation. Moreover, module optoMLKL significantly enhances innate immune responses by promoting release iDAMPs cDAMPs, which are critical initiating Furthermore, exhibits effects when activated patient-derived pancreatic cancer organoids, highlighting clinical application. These findings will pave way innovative therapies leveraging optogenetic approaches precisely enhance necroptosis.

Language: Английский

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Integrating spatial and single-cell transcriptomes reveals the role of COL1A2(+) MMP1(+/-) cancer-associated fibroblasts in ER-positive breast cancer

Cancer Cell International, Journal Year: 2025, Volume and Issue: 25(1)

Published: March 7, 2025

Cancer-associated fibroblasts (CAFs) are highly heterogeneous cells and important components of the breast tumor microenvironment (TME). However, their role clinical value in ER-positive cancer have not been fully clarified. Our study aims to comprehensively characterize heterogeneity, potential biological functions, molecular mechanisms CAFs within using multi-omics data, provide new strategies for diagnosis treatment patients. In this study, we found that COL1A2(+) MMP1(+) MMP1(-) were associated with unfavorable prognosis. The dynamic evolution cell-cell communications analyzed, revealing MMP1(+/-) show extensive crosstalk tumor-associated macrophages (TAMs), contributing an immunosuppressive TME. Moreover, somatic mutation TP53 may be a indicator evaluating infiltration CAFs. Finally, MRI-based radiomic model was constructed estimate abundance these conclusion, our findings theoretical basis targeting offer noninvasive approach evaluate level

Language: Английский

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Current advancement of immune function paradox of tumour-infiltrating cells and their immunotherapeutic targets: a mini-review

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Language: Английский

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Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: March 14, 2025

Abstract Immunotherapy targeting immune checkpoints has gained traction across various cancer types in clinical settings due to its notable advantages. Despite this, the overall response rates among patients remain modest, alongside issues of drug resistance and adverse effects. Hence, there is a pressing need enhance checkpoint blockade (ICB) therapies. Post-translational modifications (PTMs) are crucial for protein functionality. Recent research emphasizes their pivotal role regulation, directly impacting expression function these key proteins. This review delves into influence significant PTMs—ubiquitination, phosphorylation, glycosylation—on signaling. By modifications, novel immunotherapeutic strategies have emerged, paving way advancements optimizing therapies future.

Language: Английский

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Tumor Microenvironment Dynamics of Triple-Negative Breast Cancer Under Radiation Therapy

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2795 - 2795

Published: March 20, 2025

Triple-negative breast cancer (TNBC) is an aggressive subtype of characterized by the absence estrogen receptors (ER), progesterone (PR), and HER2 expression. While TNBC relatively less common, accounting for only 10–15% initial diagnosis, due to its nature, it carries a worse prognosis in comparison hormone receptor-positive counterparts. Despite significant advancements screening, treatment cancer, remains important public health burden. Following with chemotherapy, surgery, radiation, over 40% patients experience relapse within 3 years achieve least benefit from post-mastectomy radiation. The tumor microenvironment environment (TME) pivotal initiation, progression, immune evasion, resistance, prognosis. TME complex network that consists cells, non-immune soluble factors located region adjacent modulates therapeutic response differentially between TNBC. mechanisms underlying radiation resistance remain unclear, immunosuppressive has been implicated chemotherapeutic resistance. Radiation therapy (RT) known alter TME; however, changes elicited are poorly date, whether these contribute unknown. This review delves into distinct characteristics TME, explores how RT influences dynamics, examines radiosensitization, radioresistance, responses.

Language: Английский

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Expanding the Therapeutic Reach of Chimeric Antigen Receptor T-Cells and Bispecific T-Cell Engagers Across Solid Tumors

JCO Precision Oncology, Journal Year: 2025, Volume and Issue: 9

Published: March 1, 2025

The introduction of T-cell–based therapeutics in hematologic malignancies has led to improvements outcomes for patients with acute leukemia, lymphoma, and multiple myeloma. To date, the Food Drug Administration (FDA) approved seven chimeric antigen receptor-T (CAR-T) cell therapies bispecific T-cell engagers (BiTEs) across a variety malignancies; however, extension CAR-T BiTEs solid tumor arena been somewhat limited. In this review, we discuss landmark data that commercialization four novel FDA-approved malignancies, including tarlatamab small lung cancer, afamitresgene autoleucel synovial sarcoma, lifileucel metastatic melanoma, tebentafusp uveal melanoma. We targetable landscape under investigation malignancies. explore translational potential various CARs active investigation, human epidermal growth factor receptor 2–directed breast prostate stem antigen–directed (EGFR)-IL13Ra2 EGFR-vIII glioblastoma, GD2-directed neuroblastoma. glean from lessons learned existing emphasize solutions toward facilitating clinical rollout tumors, scalability meet growing needs oncology. Some include addressing on-target, off-tumor toxicity; improving manufacturing CARs; optimizing tissue-specific microenvironment by combating immune desert tumors; discovering natural neoantigens non–self-epitopes generated tumor-specific mutations. These concepts can help provide transformative benefits coming years.

Language: Английский

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Mapping immunotherapy potential: spatial transcriptomics in the unraveling of tumor-immune microenvironments in head and neck squamous cell carcinoma

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 8, 2025

Head and neck squamous cell carcinoma (HNSCC) often exhibits poor response rates to immune checkpoint inhibitor (ICI) therapies, largely owing the intricate composition spatial organization of cells within tumor-immune microenvironment (TIME). The diversity populations, their relationships, dynamic interactions significantly influence immunosuppressive nature TIME, thereby limiting efficacy immunotherapy. To address these challenges enhance therapeutic potential ICIs in HNSCC, a comprehensive analysis TIME is essential. Spatial transcriptomics (ST), cutting-edge technology, enables high-resolution mapping gene expression context tumor, providing critical insights into functional roles TIME. This review highlights importance ST uncovering complexities HNSCC proposes strategies for leveraging develop more effective immunotherapeutic approaches. By integrating molecular information, this aims pave way personalized precision-based treatments ultimately improving patient outcomes.

Language: Английский

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