Search Results (323)

Immunotherapy, especially immune checkpoint inhibitors (ICIs), has become one of the core therapeutic approaches in cancer in recent years. It demonstrates remarkable efficacy in the treatment of melanoma and lung cancer. Conversely, its use in treating gastric cancer (GC) is not associated with considerable benefits. The high heterogeneity of GC and the tumor microenvironment (TME) may directly influence this phenomenon. This review focuses on the correlation between Helicobacter pylori (H. pylori) infection, gastric physiology, and molecular subtype-specific induction pathways, with emphasis on the unique metabolic features of GC. It explores the connection of H. pylori infection, gastric physiologic functions, and molecular subtype-specific induction mechanism of GC with the special metabolism of GC. It also explains the relationship between immune metabolic reprogramming and the suppressive TME in GC. Crucially, we summarize emerging therapeutic strategies targeting metabolic vulnerabilities. Furthermore, we explore the potential of subtype-guided metabolic therapies to overcome the challenges of the immunosuppressive tumor microenvironment in GC. Full article

Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53-mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology of TP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody–drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-κB, CCRL2, and HIF-1α), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53-mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need. Full article

Lactic acid accumulates in the tumour microenvironment (TME) at concentrations reaching up to 40 mM. Initially, lactic acid was considered merely a metabolic by-product of aerobic glycolysis, a phenomenon commonly referred to as the Warburg effect and observed in the majority of tumours. Recent evidence, however, has demonstrated that lactic acid is not merely a waste product; rather, it plays a pivotal role in tumour biology. High plasma lactic acid levels correlate with increased metastatic potential and lower survival rates. Elevated lactic acid levels in the TME have been shown to suppress antitumour immune responses, facilitate both metastasis and cellular senescence, and might modulate gene expression through novel epigenetic mechanisms such as histone lactylation. This review aims to summarize current knowledge on the multifaceted impact of elevated lactic acid in the TME on tumour progression and biology. Full article

Bone metastases mark a critical and often terminal phase in cancer progression, where disseminated tumor cells (DTCs) manage to infiltrate and exploit the complex microenvironments of the bone marrow. While most current therapies focus on the well-known late-stage “vicious cycle” of osteolysis, they often overlook the earlier stages, namely, tumor cell colonization and dormancy. During these early phases, cancer cells co-opt hematopoietic stem cell (HSC) niches, using them as sanctuaries for long-term survival. In this review, we bring together emerging insights that highlight a trio of underappreciated cellular players in this metastatic takeover: megakaryocytes, erythroid lineage cells, and perivascular stromal subsets. Far from being passive bystanders, these cells actively shape the metastatic niche. For instance, megakaryocytes and platelets go beyond their role in transport; they orchestrate immune evasion and dormancy through mechanisms such as transforming growth factor-β1 (TGF-β1) signaling and the physical shielding of tumor cells. In parallel, we uncover a distinct “erythroid-immune” axis: here, stress-induced CD71⁺ erythroid progenitors suppress T-cell responses via arginase-mediated nutrient depletion and checkpoint engagement, forming a potent metabolic barrier against immune attack. Furthermore, leptin receptor–positive (LepR⁺) perivascular stromal cells emerge as key structural players. These stromal subsets not only act as anchoring points for DTCs but also maintain them in protective vascular zones via CXCL12 chemokine gradients. Altogether, these findings reveal that the metastatic bone marrow niche is not static; it is a highly dynamic, multi-lineage ecosystem. By mapping these intricate cellular interactions, we argue for a paradigm shift: targeting these early and cooperative crosstalk, whether through glycoprotein-A repetitions predominant (GARP) blockade, metabolic reprogramming, or other niche-disruptive strategies, could unlock new therapeutic avenues and prevent metastatic relapse at its root. Full article

Lung cancer remains one of the most prevalent and lethal malignancies worldwide. NSCLC, which constitutes approximately 85% of cases, continues to exhibit a poor prognosis despite advancements in therapeutic interventions, underscoring the urgent necessity to elucidate its molecular mechanisms and identify novel therapeutic targets. CD36, a multifunctional transmembrane glycoprotein, is integral to lipid uptake, immune recognition, inflammatory regulation, molecular adhesion, and apoptosis. Increasing evidence implicates CD36 in the progression of various cancers. In the context of lung cancer, CD36 facilitates tumorigenesis through multiple pathways, including the remodeling of tumor cell lipid metabolism, reprogramming of tumor-associated macrophages, and modulation of immune cell functions such as those of Tregs and CD8⁺ T cells. Additionally, CD36 is intricately linked with the function of cancer-associated fibroblasts and the remodeling of the tumor stromal microvasculature. This systematic review synthesizes the mechanisms by which CD36 contributes to NSCLC proliferation, migration, epithelial–mesenchymal transition, and modulation of the tumor microenvironment. Furthermore, we explore emerging therapeutic strategies that target CD36. Regulating CD36 expression effectively intervenes in the malignant behavior of NSCLC, underscoring its potential as a promising therapeutic target and prognostic marker. Full article

With the intensification of global population aging, the co-morbidity rate of periodontitis and osteoporosis has significantly increased. The two are pathologically intertwined, forming a vicious cycle characterized by bone immunoregulatory dysfunction in the periodontal microenvironment, abnormal accumulation of reactive oxygen species (ROS), and disruption of bone homeostasis. Conventional mechanical debridement and anti-infective therapy can reduce the pathogen load, but in some patients, it remains challenging to achieve long-term stable control of inflammation and bone resorption. Furthermore, abnormal bone metabolism in the context of osteoporosis further weakens the osteogenic response during the repair phase, limiting the efficacy of these treatments. Bioinspired cell membrane-coated nanoparticles (CMNPs) have emerged as an innovative technological platform. By mimicking the biointerface properties of source cells—such as red blood cells, platelets, white blood cells, stem cells, and their exosomes—CMNPs enable targeted drug delivery, prolonged circulation within the body, and intelligent responses to pathological microenvironments. This review systematically explores how biomimetic design leverages the advantages of natural biological membranes to address challenges in therapeutic site enrichment and tissue penetration, in vivo circulation stability and effective exposure maintenance, and oxidative stress and immune microenvironment intervention, as well as functional regeneration supported by osteogenesis and angiogenesis. Additionally, we conducted an in-depth analysis of the key challenges encountered in translating preclinical research findings into clinical applications within this field, including issues such as the feasibility of large-scale production, batch-to-batch consistency, and long-term biosafety. This review lays a solid theoretical foundation for advancing the clinical translation of synergistic treatment strategies for periodontitis with osteoporosis and provides a clear research and development pathway. Full article

The insulin-like growth factor (IGF) axis orchestrates hepatic development, regeneration, and metabolism, yet the roles of individual IGF-binding proteins (IGFBPs) remain incompletely defined. IGFBP-6, a high-affinity, IGF-II-preferring binding protein, has emerged as a context-dependent modulator of IGF bioavailability and cell signaling with additional IGF-independent actions. This review synthesizes current evidence on IGFBP-6 in liver biology and disease. We first outline hepatic expression, regulation, and post-translational processing of IGFBP-6 across development, homeostasis, and injury, and summarize its effects on canonical IGF-II/IGF1R signaling and downstream phosphatidylinositol 3-kinase—protein kinase B (PI3K–AKT) and rat sarcoma—mitogen-activated protein kinase (RAS–MAPK) pathways. We then evaluate experimental and clinical data linking IGFBP-6 to steatotic liver disease, inflammation, and fibrogenesis, including putative roles in hepatocyte stress responses, stellate cell activation, and extracellular matrix remodeling. Finally, we examine IGFBP-6 in primary liver cancers—hepatocellular carcinoma and cholangiocarcinoma—highlighting evidence for tumor-suppressive versus pro-migratory activities, potential crosstalk with hypoxia, Wnt/β-catenin and TGF-β signaling, and interactions with the tumor immune microenvironment. Across conditions, we assess the translational potential of IGFBP-6 as a circulating or tissue biomarker, its utility for patient stratification, and prospects for therapeutic targeting—either by modulating IGF-II sequestration or exploiting IGF-independent mechanisms. We conclude by identifying key knowledge gaps, methodological limitations, and priorities for future studies, including standardized measurement, cell-type-resolved profiling, and in vivo perturbation in clinically relevant models. Collectively, the review positions IGFBP-6 as a nuanced regulator of liver pathophysiology and a promising, yet underexplored, lever for diagnosis and therapy. Full article

Advanced prostate cancer, particularly castration-resistant disease, remains challenging to treat due to intratumoral heterogeneity, immune exclusion, and a suppressive tumor microenvironment. Within this ecosystem, cancer-associated fibroblasts shape tumor–stroma communication, but their marked heterogeneity and plasticity complicate classification and make indiscriminate fibroblast depletion potentially ineffective or even harmful. This review summarizes recent progress in fibroblast origins, functional subtypes, and fibroblast-driven mechanisms that promote tumor progression and therapy resistance, as well as emerging therapeutic opportunities in prostate cancer. We conducted a structured literature search of PubMed, ScienceDirect, and major publisher platforms (including Nature and SpringerLink) from database inception to 15 February 2025, supplemented by targeted manual screening of reference lists. Evidence from single-cell/spatial-omics and mechanistic studies indicates that prostate tumors contain multiple fibroblast programs that occupy distinct niches yet can interconvert. Across these studies, it was found that these fibroblasts contribute to immune suppression, extracellular matrix remodeling and stromal barrier formation, angiogenesis, and metabolic support, collectively limiting drug penetration and reinforcing immune evasion; therapeutic pressure can further rewire fibroblast states and resistance-associated signaling. Overall, the literature supports a shift toward function- and subtype-directed intervention rather than “one-size-fits-all” targeting, with promising directions including precision targeting and reversible reprogramming, rational combination strategies, and localized delivery approaches that reduce stromal barriers while preserving tissue homeostasis in high-risk and treatment-refractory prostate cancer. Full article

Breast cancer, the most prevalent malignant tumor in women, is closely linked to the human microbiota. The microbiome participates throughout breast cancer pathogenesis, including its occurrence, progression, response to anti-tumor therapies, and treatment-related complications. This review examines the central hypothesis that microbiome-driven inflammatory and immune mechanisms shape breast cancer progression through two key pathways: systemic immune-inflammatory regulation and local tumor microenvironment remodeling. Furthermore, microorganisms and their metabolites modulate systemic treatments by interfering with drug metabolism and altering systemic or local immune-inflammatory environments. Targeting the microbiota represents a promising strategy for enhancing anticancer efficacy and reducing treatment-related complications. This review aims to advance the understanding of the etiology and disease progression of breast cancer from the perspective of microbial-regulated inflammation and immunity, offering new insights for its prevention and treatment. Full article

The acute gouty arthritis (AGA) to chronic gouty arthritis (CGA) transition is a critical phase leading to irreversible joint damage and systemic complications. However, current molecular mechanism investigations have remained limited to single-omics approaches that lack comprehensive multi-omics explorations. We integrate high-depth data-independent acquisition (DIA) proteomics and untargeted metabolomics to analyze serum samples from healthy controls (n =28), AGA (n = 31), and CGA (n = 14) patients to address this gap. Through differential expression analysis, we identified nine persistently dysregulated pivotal proteins with robust discriminative capacity, including the urate excretion regulator ZBTB20 and inflammation/immune-related proteins (GUCY1A2, CNDP1, LYZ, SERPINA5, GSN). Additionally, 11 consistently altered core metabolites with diagnostic potential were detected, indicating perturbations in sex hormones, thyroid hormones, gut microbiota-derived metabolites, environmental exposures, and nutritional factors. Multi-omics KEGG enrichment analysis highlighted thyroid hormone synthesis, AMPK signaling pathway, and taurine and hypotaurine metabolism as central pathways. Correlation network analysis further revealed significant immune dysregulation, illustrating an evolution from acute immune activation to chronic inflammation during AGA-to-CGA progression. Our study establishes that a coordinated disruption of the thyroid hormone–AMPK–taurine metabolic axis and concomitant immune microenvironment remodeling is associated with chronic gout development. These findings provide critical targets for developing early diagnostic indicators and targeted interventions for CGA. Full article

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm for hepatocellular carcinoma (HCC), establishing them as the cornerstone of systemic therapy for advanced stages of the disease. Nonetheless, the response rate remains limited, with only 15% to 20% of HCC patients benefiting from ICIs. Approximately 70% to 80% of cases exhibit resistance to anti-PD1 therapy. Therefore, exploring the biomarkers that can be used to identify the response of patients with HCC to immunotherapy and elucidating the potential mechanisms of immunotherapy resistance contribute to the development of predictive biomarkers and are significant for overcoming resistance and enhancing treatment efficacy. This review synthesizes the current understanding of both primary and acquired resistance mechanisms to ICIs in HCC. Compared with existing reviews, this article uniquely integrates the latest evidence on metabolic reprogramming and tumor immune microenvironment (TIME) remodeling in HCC. It also emphasizes the mechanistic crosstalk between oncogenic signaling, immunosuppression, and metabolic adaptation, providing an updated and more comprehensive framework for understanding ICI resistance. It provides a valuable reference for future research aimed at overcoming therapeutic resistance in this malignancy. Full article

The ovary, as the primary organ responsible for reproduction and new life, plays a central role in female development, maturation, and health. Neoplasms arising from the ovary and its associated tissues exhibit substantial heterogeneity in their histopathological and molecular profiles, many of which remain poorly understood. This review aims to summarize recent advances in the understanding of genetic alterations underlying ovarian neoplasms and to explore therapeutic strategies informed by molecular biomarkers and tumor microenvironmental factors. A comprehensive literature search was performed, focusing on genomic alterations, biomarker-guided therapies, and tumor microenvironmental modulation in ovarian cancers. Emphasis was placed on studies addressing lipid mediator pathways and their roles in immune regulation and therapeutic response. Based on diagnostic classifications, recurrent alterations in TP53, MYC, PIK3CA, and KRAS are consistently observed across epithelial and germ cell ovarian tumors, whereas non-epithelial subtypes such as sex cord–stromal tumors (SCSTs) and small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), are predominantly associated with ARID1A and SMARCA4 mutations, respectively. These findings highlight distinct pathogenic mechanisms linked to specific genetic alterations and reveal potential therapeutic vulnerabilities. Moreover, lipid metabolism has been closely implicated in immune surveillance through STING signaling cascades within innate immune cells, suggesting that lipid mediators and their associated genes may represent promising therapeutic targets in ovarian cancers (OCs). Targeting lipid mediators could be particularly effective in relapsed OCs, as modulating innate immune cells within the tumor microenvironment (TME) may enhance immune surveillance and improve antitumor responses. Integrating genetic and microenvironmental insights offers a promising direction for developing more effective and personalized therapeutic strategies in OC. Full article

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs. Full article

This article presents a conceptual perspective proposing that hypoxia acts as a unifying regulator of plasma membrane phosphohydrolases. We propose that oxygen sensing at the cell surface integrates adenosine and phosphate metabolism to sustain tumour adaptation. Within the oxygen- and nutrient-deprived tumour microenvironment, inorganic phosphate (Pi) and adenosine function as metabolic substrates and signalling mediators that promote cell proliferation, survival, and immune evasion. Stabilisation of hypoxia-inducible factor-1α (HIF-1α) enhances the expression and catalytic activity of specific phosphohydrolases, notably the ectonucleotidases CD39 (NTPDase1) and CD73 (ecto-5′-nucleotidase), which drive adenosine accumulation and immunosuppression. Conversely, the activity of transmembrane prostatic acid phosphatase (TM-PAP), responsible for hydrolysing phosphate esters such as p-nitrophenylphosphate (pNPP) and AMP, is inhibited under hypoxia through oxidative and kinase-dependent mechanisms. Collectively, these mechanisms characterise the plasma membrane as a dynamic metabolic interface, where oxygen sensing coordinates adenosine and phosphate turnover, thereby promoting tumour adaptation across hypoxic environments. We propose that hypoxia orchestrates a dual regulatory loop connecting adenosine accumulation and phosphate turnover at the tumour cell surface, providing a conceptual basis for future mechanistic studies. Full article

HER2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase which is overexpressed in ~20% of patients with oesophagogastric adenocarcinoma (EGA). HER2 represents a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, which plays a crucial role in cell proliferation, survival, and differentiation. HER2 significantly influences the tumour microenvironment (TME) through various mechanisms, creating a niche that supports tumour progression, immune evasion, and therapeutic resistance. In HER2-positive EGA, aberrant signalling pathways, such as PI3K/AKT and MAPK/ERK, enhance tumour cell survival and proliferation, whilst upregulation of angiogenic factors like VEGF fosters vascularization, meeting a tumour’s metabolic demands and facilitating its proliferation. HER2 also modulates the tumour immune microenvironment (TIME) by downregulating MHC molecules and recruiting immunosuppressive cells, including regulatory T-cells (T-reg) and tumour-associated macrophages (TAMs), which release cytokines that further inhibit anti-tumour immune responses. Together, these factors foster a pro-inflammatory, immunosuppressive microenvironment that underpins resistance to HER2-targeted therapies. As more HER2-directed treatments become available, such as trastuzumab–deruxtecan (T-DXd), gaining a deeper understanding of the multifaceted influence of HER2 on the TME in EGA will be crucial for the development of improved targeted treatments that can overcome these challenges and lead to advancements in targeted treatment for HER2-overexpressing EGA. This review provides a comprehensive overview of the impact of HER2 on the TME in EGA and highlights the challenge it represents as well as the opportunity for novel therapeutic development and the implications for patients in terms of clinicopathological outcomes. Full article