Search Results (1,053)

Tumor acidity is a hallmark of the tumor microenvironment (TME) and has been widely regarded as a promising therapeutic target due to its ubiquity, functional relevance, and apparent selectivity for malignant tissues. Extensive preclinical studies have demonstrated that targeting tumor acidity—through inhibition of lactate production, blockade of proton transport, systemic buffering, and pH-responsive drug delivery—can suppress tumor growth, reduce metastasis, and enhance antitumor immunity. However, despite strong mechanistic rationale and consistent preclinical efficacy, these strategies have failed to achieve meaningful and durable clinical success. In this review, we examine the underlying reasons for this translational discrepancy. We highlight key mechanistic and systemic barriers, including spatial heterogeneity of tumor pH, temporal dynamics and adaptive evolution, metabolic plasticity, redundancy of pH-regulating systems, systemic physiological constraints, and drug delivery limitations in hypoxic and acidic regions. We further argue that tumor acidity is not a sufficient standalone driver of tumor progression but rather a feature of a complex and adaptive system shaped by metabolic and microenvironmental interactions. Finally, we discuss emerging strategies that may overcome these limitations, including combination therapies integrating metabolic targeting with immunotherapy, pH-responsive drug delivery systems, microenvironment reprogramming, and biomarker-guided patient stratification. Overall, current evidence suggests that future therapeutic approaches may benefit more from exploiting tumor acidity as a feature of the tumor microenvironment rather than attempting to directly neutralize it. Full article

Background: Effective vaccines are essential to overcome the limitations of livestock immunisation, particularly in low- and middle-income countries (LMICs), where scalable, thermostable, and easy-to-administer solutions are needed. Nanoparticle-based delivery systems, such as the Spontaneous Nanoliposome Antigen Particle (SNAP) technology using CoPoP liposomes, offer a promising alternative for subunit vaccine development, although their performance in large animal species remains poorly characterised. CoPoP enables the rapid non-covalent multimeric display of His-tagged protein antigens combined with immunomodulators on liposomes incorporating cobalt porphyrin–phospholipid (CoPoP). Objective: To evaluate the immunogenicity of CoPoP-based liposomes delivering the Theileria parva p67C antigen in cattle and compare their performance in murine models. Methods: Cattle and mice were immunised with p67C formulated in CoPoP liposomes incorporating QS-21 and/or PHAD immunomodulators. Humoral and cellular responses were assessed. Parallel in vitro stimulation of bovine PBMC with Quil-A was used to investigate the mechanistic effects of saponins on bovine cells. Results: CoPoP liposome formulations did not improve p67C immunogenicity in cattle, with antibody responses at least two-fold lower than previously reported results and no detectable cellular responses. In contrast, the same platform induced up to 2000-fold higher antibody titres in mice. This disparity is likely driven by differences in antigen dose relative to body mass, tissue architecture, lymphatic accessibility, and innate immune signalling differences. PHAD-mediated TLR4 activation appeared less effective in cattle, whereas QS-21 induced a broader immune activation, likely through conserved inflammasome pathways. Despite limited immunogenicity, antigen presentation by CoPoP liposomes was preserved. Conclusions: SNAP-based CoPoP liposomes showed strong immunogenicity in mice but limited efficacy in cattle, highlighting the challenges of cross-species translation. Optimisation of antigen dose and adjuvant selection for the targeted species is required, with QS-21 representing a more promising candidate than the TLR4 agonist. The scalability and versatility of SNAP technology support its continued development for multivalent livestock vaccines. Full article

Insects represent powerful experimental systems for investigating host–microorganism interactions, providing valuable insights into bacterial pathogenicity, immune regulation, symbiosis, and antimicrobial discovery. This review examines the complex relationships between insects and bacteria, focusing on the mechanisms that control infection, immune activation, and microbial adaptation. Particular attention is given to the routes of pathogen entry and to the conserved innate immune pathways that coordinate host defenses, including the Toll, Imd, Duox, and Jak/Stat signaling cascades. The review illustrates how bacterial pathogens exploit toxins, immune evasion strategies, and metabolic adaptation to overcome host defenses, while insects rely on tightly regulated cellular and humoral responses, antimicrobial peptides, melanization, and microbiota-mediated homeostasis. Interactions between pathogenic and commensal bacteria in the insect gut are discussed in the context of immune tolerance, dysbiosis, and ecological adaptation. The dual role of bacterial virulence factors in both pathogenesis and symbiosis is highlighted through examples involving entomopathogenic bacteria such as Photorhabdus spp., Xenorhabdus spp., and Bacillus thuringiensis. In addition, the review summarizes the use of insect models, including Drosophila melanogaster, Galleria mellonella, Bombyx mori, and Apis mellifera, in experimental infections aimed at studying virulence mechanisms, host immune responses, and antimicrobial efficacy. Finally, multi-omic approaches, including transcriptomics, metabolomics, epigenomics, and single-cell technologies are discussed as transformative tools for dissecting host–microbe interactions at molecular and systems levels. Overall, insect–bacteria interactions emerge as dynamic and evolutionarily shaped systems in which immunity, metabolism, microbiota composition, and environmental factors are closely interconnected, offering important perspectives for both basic research and the development of sustainable biocontrol and antimicrobial strategies. Full article

Endometrial cancer (EC) is increasingly recognized as a heterogeneous disease, yet current treatment strategies often fail to explain why tumors with similar molecular profiles respond differently or develop resistance. This gap points to regulatory mechanisms beyond static genomic alterations. Epigenetic dysregulation through DNA methylation, histone modification, and non-coding RNA (ncRNAs) networks acts as a dynamic and reversible system that governs how tumors adapt under therapeutic pressure. In EC, alterations affecting key regulators such as MLH1, PTEN, and hormone receptors directly influence sensitivity to immunotherapy, targeted therapy, and endocrine treatment, defining treatment-responsive and treatment-resistant states. These observations shift the role of epigenetics from a descriptive feature of tumor biology to a determinant of therapeutic behaviour. Epigenetic states influence immune recognition, pathway activation, and cell cycle control, thereby shaping response to chemotherapy and immune checkpoint blockade. Biomarkers derived from these alterations, including methylation signatures and circulating RNAs, offer opportunities for patient stratification and longitudinal monitoring of treatment response. Therapeutically, targeting epigenetic regulators provides a strategy to reverse resistance and restore treatment sensitivity. DNA methyltransferase and histone deacetylase inhibitors, particularly in combination with established therapies, have shown potential to enhance treatment efficacy. Emerging approaches, including locus-specific epigenetic editing and liquid biopsy–guided monitoring, further support adaptive treatment strategies. Integrating epigenetic reprogramming into clinical decision-making offers a practical path toward improving treatment response and overcoming resistance in EC. Here, we propose an Epigenetic State–Response Framework (ESRF) in which dynamic epigenetic states define treatment-sensitive and resistant phenotypes, map to specific therapeutic vulnerabilities, and can be actively reprogrammed to restore treatment response. Full article

Cancer immunotherapy has transformed oncology by harnessing the immune system to recognize and eliminate malignant cells. However, many cancers exhibit limited or variable responses to this class of treatment due to insufficient antigen presentation and impaired interferon (IFN) signaling, creating an immunologically “cold” tumor microenvironment (TME) characterized by poor immune cell infiltration and treatment resistance. Viral mimicry has emerged as a therapeutic strategy to overcome these limitations by reactivating innate antiviral pathways within tumor cells. Viral mimicry occurs through the reactivation of endogenous retroviruses (ERVs) and other retrotransposons (e.g., LINE-1), which subsequently stimulate downstream nucleic acid sensing pathways. The resulting type I/III IFN responses restore antigen presentation and attract cytotoxic immune cells, sensitizing resistant tumors to immunotherapy. However, systemic stimulation of these pathways can trigger context-dependent inflammation and adaptive resistance, highlighting the need for temporal and spatial control. In this review, we examine the mechanistic foundation and clinical trajectory of viral mimicry, with an emphasis on its potential integration with established treatments and engineered immune cell platforms. By identifying the molecular and clinical gaps, viral mimicry can be harnessed to enhance tumor-specific immune activation and overcome treatment resistance in cancer immunotherapy. Full article

Photodynamic therapy (PDT) occupies an important place in the arsenal of cancer treatment modalities; however, its efficacy is primarily limited by the local nature of its effects and by tumor cell resistance. The aim of this review is to analyze the fundamental principles and biological consequences of PDT, to summarize current data on the molecular and cellular mechanisms determining its efficacy, and to consider strategies for overcoming its limitations. Particular attention is paid to the mechanisms underlying resistance development and to the role of switching from non-immunogenic to immunogenic cell death in shaping the antitumor response. The potential integration of PDT with dendritic cell vaccination is considered a promising strategy for overcoming these limitations. The potential of vaccine-based approaches to activate specific antitumor immunity in aggressive cancers is highlighted, with emphasis on the advantages of dendritic cell vaccines in addressing the limitations of conventional PDT. Full article

Globally, Mycobacterium tuberculosis (Mtb) remains the leading cause of death from a single infectious agent. The only licensed vaccine, Bacillus Calmette–Guérin (BCG), was developed over a century ago and does not provide consistent protection against pulmonary tuberculosis (TB). Efforts to develop more effective vaccines are hindered by an incomplete understanding of the correlates of protection and by the pathogen’s sophisticated immune-evasion strategies. Mtb systematically undermines host defenses, reprograms host cell biology, and interferes with cell–cell communication to establish a permissive niche and sustain chronic infection. An effective vaccine must elicit immune responses capable of overcoming these bacterial strategies across diverse host and pathogen backgrounds. Traditional approaches focused on boosting T cell responses have proven inadequate. In this review, we summarize innate and adaptive immune mechanisms that contain Mtb, examine how bacterial immune subversion and host–pathogen heterogeneity complicate vaccine design, and highlight emerging concepts and strategies to guide TB vaccine development. Full article

Difficult-to-treat systemic lupus erythematosus (D2T-SLE) remains a major unmet challenge in contemporary lupus care, yet it continues to be defined predominantly by clinical non-response rather than underlying biology. Current biomarkers largely quantify inflammatory burden, immune complex activity, or organ damage and do not reliably capture persistent activation of pathogenic pathways under therapy. Emerging multi-omics, single-cell, and longitudinal studies suggest that, in a subset of patients, apparent treatment failure may reflect incomplete attenuation of dominant immune circuits rather than uniformly elevated inflammation. We propose molecular refractoriness in systemic lupus erythematosus (SLE) as sustained, pathway-level immune activity despite apparently adequate, mechanism-directed therapy. We outline the major immune programs implicated in this process—including interferon-enriched, B-cell/plasmablast-associated, neutrophil extracellular trap (NET)-related, cytotoxic T-cell, and cytokine-associated states—and discuss their relevance for biomarker development and precision trial design. Importantly, we emphasize that interferon gene signatures (IGS) should be interpreted as context-dependent and non-specific markers of interferon responsiveness, reflecting combined activity of type I, II, and III interferons, and functioning primarily as predictive rather than mechanistic biomarkers. We further highlight critical limitations of a purely endotype-based model, including the need to distinguish true molecular refractoriness from damage-dominant and pseudo-refractory states, as well as the emerging role of immune-reset strategies such as cluster of differentiation 19 (CD19)-directed chimeric antigen receptor T-cell (CAR-T) therapy, which may overcome refractoriness independently of specific pathway dominance. These observations suggest that difficult-to-treat SLE encompasses biologically heterogeneous states that may not be fully captured by pathway-resolved stratification alone. Reframing D2T-SLE as a biologically heterogeneous state of incomplete immune attenuation may help bridge the gap between clinical treatment failure and mechanism-informed precision medicine in systemic lupus erythematosus. Full article

Dendritic cells (DCs) are central to cancer immunity, orchestrating both innate and adaptive immune responses. In melanoma and other solid tumors, however, their function is often impaired within the tumor microenvironment (TME), leading to weakened antitumor immunity and diminished responses to immune checkpoint inhibitors (ICIs) and adoptive tumor-infiltrating lymphocyte (TIL) therapy. Among the various cell-based immunotherapy approaches, DC therapy—particularly using blood-derived conventional DCs (cDCs)—holds considerable promise. Compared with traditional monocyte-derived DCs (moDCs), cDCs exhibit superior antigen processing and cross-presentation capacities. The therapeutic application of cDCs was initially pioneered in vaccine strategies involving ex vivo antigen loading and maturation, followed by administration to lymph nodes. More recently, intratumoral (IT) cDC immunotherapy has emerged as a strategy to reinvigorate the cancer-immunity cycle by engaging the full repertoire of tumor-associated antigens while limiting systemic toxicity. This review discusses the underlying biological mechanisms and summarizes the clinical outcomes of IT DC therapy in cancer. Notably, combination approaches incorporating IT cDCs with ICIs, oncolytic viruses, synthetic adjuvants, radiation, or cryotherapy are emerging as promising strategies to overcome both primary and acquired resistance to ICI monotherapy. Collectively, these findings highlight the potential of integrating IT cDC therapy with complementary immunotherapies in next-generation, cross-tumor treatment strategies. Full article

Hematological malignancies, including multiple myeloma (MM), leukemia, and lymphoma, represent a major global health burden, accounting for approximately 6.6% of all cancer cases and contributing to significant mortality. The evolutionary conserved WNT/β-catenin signaling pathway is a critical regulator of normal hematopoietic stem cell homeostasis, and its dysregulation is a hallmark of various hematological malignancies. Aberrant activation through mutations, overexpression of ligands, or disruption of the destruction complex drives uncontrolled proliferation, impaired differentiation, and therapeutic resistance to therapy in acute and chronic leukemias, lymphomas, and multiple myeloma. Therapeutic interventions targeting this pathway, such as GSK-3 inhibitors, β-catenin antagonists, and small molecules like CWP291 and salinomycin, have demonstrated promising antitumor effects. Furthermore, combining WNT/β-catenin inhibition with targeted or epigenetic therapies, such as venetoclax and chidamide, can produce synergistic antitumor effects and overcome chemoresistance. Despite this potential, clinical translation is hampered by on-target toxicities in healthy tissues, pathway complexity, and a lack of predictive biomarkers. We conclude that the future of WNT-directed therapy lies in developing biomarker-selective agents, advanced drug delivery systems to improve specificity, and exploring novel combinations with immunotherapy to harness the anti-tumor immune response. Full article

Baicalin is a natural compound sourced from Scutellaria baicalensis which possesses various biological activities. To date, a large amount of research has been conducted on the antibacterial activity and related mechanisms of baicalin, making it a promising candidate for new broad-spectrum antibacterial drugs. However, the solubility of baicalin is limited. To improve its solubility and overcome the clinical application bottleneck, researchers have developed various solubilization techniques. Therefore, this article introduces the biological characteristics of baicalin; explores its effects as an antibacterial agent on bacterial biofilms, quorum sensing, virulence factors, inflammatory responses, and the immune system; and discusses the applications of nano-carrier loading technology, cyclodextrin inclusion technology, metal ion coordination and organometallic complexation technology, and dynamic covalent hydrogel assembly technology in improving the solubility of baicalin, thereby enhancing its antibacterial activity. Full article

Background: Photodynamic therapy (PDT) has emerged as a powerful minimally invasive modality for cancer treatment. However, its efficacy as a monotherapy is often limited by oxygen dependence and limited light penetration. Combining PDT with systemic anticancer drug therapies offers a promising strategy to achieve synergistic effects and overcome resistance. Objective: This review aims to provide a systematic analysis of the mechanisms and clinical potential of combining PDT with chemotherapy, targeted therapy, and immunotherapy, focusing on recent advancements and nanotechnology-based delivery systems. Methods: A comprehensive literature search was performed using PubMed and Scopus databases. The analysis focused on peer-reviewed studies published over the last 10 years addressing synergistic molecular pathways, co-delivery nanoplatforms, and clinical trial outcomes. Results: The combination of PDT with chemotherapy enhances drug accumulation via vascular photosensitization and can overcome multi-drug resistance. Integration with immunotherapy, particularly immune checkpoint inhibitors and tumor vaccines, triggers immunogenic cell death (ICD), leading to systemic antitumor responses. Nanotechnology provides a versatile platform for the targeted co-delivery of photosensitizers and pharmacological agents, significantly reducing systemic toxicity. Conclusions: Combined PDT–drug regimens demonstrate superior therapeutic efficacy compared to monotherapies. Future clinical translation requires the standardization of dosimetry and the development of multifunctional nanomedicines to enable personalized treatment protocols. Full article

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment; however, durable responses occur in only a subset of patients, underscoring the need for robust predictive biomarkers. Serine/threonine kinase 11 (STK11) is an emerging biomarker that portends poor prognosis and predicts therapeutic resistance. Loss of STK11 disrupts AMPK signaling, leading to unchecked mTOR activation, metabolic reprogramming, angiogenesis, and epithelial–mesenchymal transition, fostering tumor progression and immune evasion. STK11 mutations frequently co-occur with KRAS and KEAP1 alterations, exhibit low PD-L1 expression, an immunosuppressive tumor microenvironment that leads to the development of PD-1/PD-L1 resistance. Clinical studies consistently demonstrate inferior outcomes with ICIs in STK11-mutant NSCLC, particularly in the presence of KRAS and KEAP1 co-mutations. Dual checkpoint inhibition combining PD-1/PD-L1 and CTLA-4 blockade shows promise in overcoming resistance, results remain inconsistent, and prospective trials are ongoing. Beyond immunotherapy, STK11 mutations confer poor outcomes across targeted therapies, including KRAS G12C inhibitors, with KEAP1 co-mutation serving as a strong negative predictor of efficacy. In this review we present an overview of STK11 function and its role in tumor biology, highlight the prognostic and predictive potential of STK11 mutations in the context of NSCLC treatment and summarize the emerging treatment strategies. Full article

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as potent modulators of immune responses during sepsis, yet their roles remain complex, alternating between protective and permissive depending on timing, tissue compartment, and inflammatory context. This review presents a historical assessment of VIP and PACAP in sepsis research, highlighting the evolution of conceptual advances across five decades. Starting in the 1980s, early studies revealed that VIP levels rise during endotoxemia and correlated with hypotension and mortality, suggesting a deleterious role. By the 1990s, research pivoted toward understanding gut-derived VIP and its interaction with nitric oxide, culminating in the classification of VIP and PACAP as “macrophage deactivating factors” that downregulate TNFα and IL-6. The 2000s further clarified their cell-specific actions through VPAC1/2 and PAC1 receptors, showing anti-inflammatory effects on both innate and adaptive immune cells, while illuminating delivery challenges overcome by liposomal encapsulation. The 2010s expanded this narrative by dissecting receptor dynamics, gut barrier regulation, and VIP’s role in neuroimmune crosstalk and thrombo-inflammation. Most recently, studies in the 2020s provide a nuanced view of how VIP suppresses inflammatory damage but also enables pathogen persistence during live bacterial infection, implicating VIP signaling in trade-offs between tolerance and clearance. Across this chronological framework, VIP and PACAP have oscillated between friend, foe, and frenemy, underscoring the importance of context in leveraging their therapeutic potential in sepsis. Full article

Cutaneous melanoma is the most lethal form of skin cancer because of its aggressiveness, rapid metastasis, and high therapeutic resistance. The 2018 World Health Organization (WHO) classification emphasized that melanoma comprises distinct subtypes defined by cumulative sun damage, site of origin, and molecular characteristics, which explain differences in mutational burden, immunogenicity, and treatment response. Immunotherapy with anti-PD-1 therapy such as nivolumab and pembrolizumab changed the therapeutic landscape by restoring CD8+ T-cell activity and improving survival. Still, many patients show primary or acquired resistance influenced by low PD-L1 expression, loss of antigen presentation, tumor metabolic plasticity, and an immunosuppressive microenvironment. Mitochondria are central to this process. They regulate ATP generation through oxidative phosphorylation (OXPHOS), redox control, apoptosis, and the metabolic programming needed for T-cell activation. In the tumor microenvironment (TME), hypoxia, nutrient restriction, and PD-1 signaling reduce mitochondrial biogenesis, increase fission and reactive oxygen species (ROS) accumulation, and lead to exhaustion and impaired effector function. Moreover, tumor cells outcompete immune cells for key nutrients such as glucose and glutamine, while increased lactate production and extracellular acidosis further suppress mitochondrial respiration in T cells. Strategies to overcome resistance include restoring oxidative metabolism, activating PGC-1α, supplying metabolic substrates, and combining checkpoint blockade with inhibitors of glycolysis or glutaminolysis to enhance the immune response. Full article