Search Results (965)

Aberrations in fibroblast growth factor receptors (FGFRs) constitute a key oncogenic mechanism across multiple solid tumors, influencing tumor initiation, therapeutic response, and clinical outcomes. This review synthesizes current knowledge on the molecular biology, signaling networks, and tumor-specific distribution of FGFR alterations, including amplifications, point mutations, and gene fusions. The mechanistic basis of FGFR-driven tumor progression is discussed, including activation of downstream signaling pathways, crosstalk with other receptor tyrosine kinases, and regulation of the tumor microenvironment, angiogenesis, and immune escape. Recent development of selective FGFR inhibitors—such as pemigatinib, erdafitinib, and futibatinib—has translated mechanistic insights into measurable clinical benefits in genomically defined patient populations. However, acquired resistance remains a major challenge, driven by secondary mutations, activation of bypass pathways, and intratumoral heterogeneity. Integration of multi-omics profiling, liquid biopsy monitoring, and biomarker-guided patient selection is essential to optimize therapeutic efficacy and overcome resistance. This review also highlights emerging therapeutic modalities, such as antibody–drug conjugates and nanotechnology-based delivery systems, which may improve target specificity and prolong therapeutic durability. By integrating molecular, translational, and clinical evidence, this review aims to establish a comprehensive framework for precision oncology strategies targeting FGFR-driven malignancies. Full article

Background: Electrochemotherapy (ECT) is a clinically validated local ablative treatment increasingly recognized for its ability to induce immunogenic cell death and stimulate antitumor immunity. Its combination with immune checkpoint inhibitors, such as anti-PD-1 antibodies, may enhance systemic immune responses and improve therapeutic efficacy, particularly in poorly immunogenic tumors. Methods: We evaluated the antitumor effectiveness of ECT combined with a murine analog of the anti-PD-1 antibody in four syngeneic murine tumor models with differing histology and immune status: WEHI fibrosarcoma, CT26 and MC38 colorectal carcinoma, and 4T1 mammary carcinoma. In vitro cytotoxicity assays assessed tumor cell sensitivity to ECT, while in vivo experiments evaluated complete response (CR) rates, immune cell infiltration, and long-term immune memory through secondary tumor challenge. Immunohistochemical analysis of CD4⁺, CD8⁺, and granzyme B⁺ effector cells. Results: In vitro, WEHI cells exhibited the highest sensitivity to ECT. In vivo, ECT monotherapy induced CRs in 100% of WEHI tumors, 60% of CT26, 17% of 4T1, and 15% of MC38. The addition of anti-PD-1 significantly enhanced outcomes in less responsive models, increasing CRs to 90% in CT26, 91% in MC38, and 53% in 4T1. Combination therapy promoted pronounced infiltration of CD4⁺, CD8⁺, and granzyme B⁺ T cells and the formation of tertiary lymphoid structure, particularly in MC38 tumors. Secondary challenge experiments confirmed long-term immune memory in CT26 and MC38 models and induced memory in 4T1, which was absent following monotherapy. Conclusions: ECT synergizes with PD-1 blockade to potentiate local and systemic antitumor immunity, overcoming immune resistance in poorly immunogenic tumors. These findings support further clinical development of ECT in combination with immune checkpoint inhibitors as a component of personalized cancer immunotherapy. Full article

Breast cancer remains the most commonly diagnosed malignancy among women worldwide and continues to pose significant therapeutic challenges, particularly in advanced and refractory disease. Although traditionally considered less immunogenic compared with other solid tumours, growing evidence demonstrates that subsets of breast cancer, particularly triple-negative and HER2-positive subtypes, exhibit immune-responsive features. This recognition has spurred the development and clinical evaluation of immunotherapeutic strategies, with immune checkpoint inhibitors (ICIs) emerging as the most prominent approach. This new class of drugs targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has demonstrated meaningful clinical activity in select patient populations, leading to regulatory approvals in combination with chemotherapy for advanced triple-negative breast cancer. Despite these advances, response rates remain modest, and the benefits are largely restricted to patients with PD-L1-positive tumours. Ongoing studies are evaluating predictive biomarkers, optimal treatment combinations, and mechanisms of resistance to expand the efficacy of ICIs across broader breast cancer subtypes. Furthermore, novel checkpoint targets such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) are under investigation, with the potential to enhance or complement PD-1/PD-L1 blockade. This review summarises the current state of knowledge on breast cancer immunotherapy with an emphasis on ICIs, highlighting key clinical trial findings, as well as emerging biomarkers of response, and strategies to overcome therapeutic resistance, if cancer cells eventually develop resistance. By integrating preclinical insights with clinical progress, we aim to provide a comprehensive overview of the evolving role of checkpoint blockade in breast cancer and outline future directions to optimise patient outcomes. Full article

Intratumoral microbiota, once considered passive bystanders, are now recognized as active modulators of the tumor immune microenvironment (TIME)—the complex network of immune cells, stromal components, and signaling molecules within tumors—and ultimately shape immunotherapy outcomes in lung cancer. This review aims to elucidate the exact roles of intratumoral microbiota in lung cancer immuno-therapy responses and the potential mechanism, offering novel perspectives for overcoming resistance. We conducted a narrative review of the literature using a PubMed and Web of Science search of articles written in English from inception to November 2025. We summarize current evidence on the characteristics of intratumoral microbiota in lung cancer and their associations with patient outcomes following immune checkpoint inhibitor (ICI) treatment. We discuss how intratumoral microbes, their metabolites, and extracellular vesicles influence and remodel TIME, thereby either promoting or counteracting ICI efficacy. Furthermore, we explore the potential of microbial signatures as predictive biomarkers and highlight microbiota-targeted strategies—including probiotics, engineered bacteria, and rational antibiotic use—to overcome resistance and enhance clinical benefits. Collectively, available data support intratumoral microbiota as crucial modulators and promising therapeutic targets in lung cancer, and decoding their multifaceted interactions may inform precision microbiota-targeting strategies to improve patient outcomes. 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

Residual cardiovascular risk remains a major challenge in coronary artery disease, even after optimal lipid-lowering and anti-inflammatory therapy. Beyond classical risk factors, persistent low-grade inflammation and fibrotic remodeling contribute to adverse outcomes that current treatments fail to fully prevent. Growing evidence highlights the glyco-inflammatory axis—the interplay between protein glycosylation-dependent signaling and inflammation—as an underappreciated contributor to residual atherosclerotic risk, largely because current therapeutic strategies do not directly target glycan-mediated mechanisms. Within this framework, Galectin-3 (Gal-3), a β-galactoside-binding lectin, has emerged as a key molecular hub linking metabolic stress, lysosomal dysfunction, and vascular remodeling. By recognizing specific glycan motifs on immune and stromal cells, Gal-3 orchestrates macrophage activation, endothelial dysfunction, and extracellular matrix deposition, thereby amplifying chronic inflammation and fibrosis. Elevated circulating Gal-3 levels are associated with plaque vulnerability and major adverse cardiovascular events, independent of lipid or C-reactive protein levels. Experimental Gal-3 inhibition reduces inflammation and fibrosis in preclinical models, supporting its therapeutic potential. This review integrates mechanistic, translational, and clinical evidence to propose Gal-3 as a missing link between intracellular stress responses and extracellular fibro-inflammatory remodeling. Targeting the Gal-3-mediated glyco-inflammatory axis may represent a novel strategy to overcome residual cardiovascular risk and achieve comprehensive vascular protection in the post-statin era. Full article

Introduction: Children with chronic kidney disease (CKD) are susceptible to infections due to impaired immunity, immunosuppressive treatments, and dialysis, which lead to increased mortality, morbidity, and hospitalization rates. Immunization is an efficient preventive strategy, but despite the long-existing guidelines, vaccination rates of children with CKD remain suboptimal. Aim: This review aims to summarize the available data on vaccine-preventable infection morbidity and vaccination coverage in children with CKD, the reasons of vulnerability and suboptimal vaccination of this population and strategies that have been proposed for their overcoming. Results: Vaccination coverage studies for children with CKD are limited and outdated but, despite their variability, they confirm suboptimal vaccine coverage. The vulnerability of children with CKD to infectious dis-eases has been better understood with advanced molecular studies of their immune re-sponse. Several barriers, some of them unique to this population, hamper adherence with vaccination guidelines. Targeted interventions at different levels that have already been tried in adults with CKD, such as enhanced communication with families, cocooning strategies for the most vulnerable, education of specialists on vaccines, and organization of vaccination teams, seem promising in improving vaccination rates and infection prevention. Conclusions: The suboptimal protection from infections of children with CKD can be improved with prioritization of vaccination in their complicated care. Full article

Epizootic hemorrhagic disease (EHD) is an important livestock disease caused by Epizootic hemorrhagic disease virus (EHDV). The recent incursion and wide distribution of EHDV in Europe have increased the need for effective vaccine candidates. Background/Objectives: The VP2 protein of EHDV forms the outer capsid layer of the virion and is essential for viral assembly and host cell entry. Owing to its antigenic properties, VP2 represents a major target for vaccine development. However, the recombinant production of VP2 is limited by low stability and poor yields, representing a significant barrier for the generation of safe and effective subunit vaccines. Methods: To overcome these limitations, the VP2 protein from EHDV serotype 8 (EHDV-8) was rationally engineered with targeted modifications at both the amino and carboxyl termini of its coding sequence. Recombinant expression was performed using a baculovirus vector-mediated system in Trichoplusia ni pupae (CrisBio^® technology), employed as living biofactories. Results: The engineering of VP2 resulted in up to a tenfold increase in protein yields compared with the wild-type sequence, while maintaining the trimeric structural integrity of the recombinant protein. Both wild-type and engineered VP2 protein variants were formulated and used to immunize IFNAR(−/−) mice, a model susceptible to EHDV infection. Both engineered and wild-type VP2 formulations elicited comparable neutralizing antibody responses in vaccinated animals. Furthermore, immunization with either formulation conferred full protection against lethal EHDV-8 challenge. Conclusions: In this work, we demonstrated that the rational engineering of the VP2 protein significantly improved recombinant expression yields in a baculovirus-based system without compromising structural integrity or immunogenicity. These findings additionally demonstrate the feasibility of producing high-quality VP2 antigens in T. ni pupae using CrisBio^® technology and support their potential application in the development of subunit vaccines against EHDV. Full article

Background/Objectives: The polypeptide N-acetylgalactosaminyltransferase (GALNT) family initiates mucin-type O-glycosylation, a post-translational modification that plays a pivotal role in cellular signaling, adhesion, and immune evasion. Dysregulated GALNT expression has been increasingly implicated in carcinogenesis. Methods: We reviewed the literature on the expression, function, and clinical relevance of GALNT isoforms across various cancers, with a focus on their mechanistic roles, biomarker potential, and therapeutic implications. Results: Aberrant GALNT expression is observed in numerous malignancies, including breast, colorectal, gastric, lung, ovarian, and hepatocellular carcinomas. Isoforms such as GALNT1, -T2, -T3, and -T14 contribute to tumorigenesis by modulating the glycosylation of mucins such as Mucin-1 (MUC1), epithelial growth factor receptors (EGFR), and other signaling proteins. These alterations promote cancer cell proliferation, metastasis, epithelial–mesenchymal transition (EMT), and chemoresistance. Deranged GALNT expression is frequently associated with poor prognosis, and certain GALNT genotypes predict treatment response. However, functional redundancy among isoforms poses challenges for selective targeting. Conclusions: Despite their strong potential as modulators of cancer progression, GALNTs face substantial limitations in terms of substrate identification, mechanistic clarity, immune relevance, and therapeutic tractability. Overcoming these challenges requires advanced glycoproteomics, development of isoform-specific tools, and integrated studies across cancer and immunology to fully harness GALNT biology for clinical benefit. Full article

Background/Objectives: The rise of immune escape variants of the SARS-CoV-2 virus has prompted the development of vaccines based on the variant’s spike antigen sequence. Since variant-specific SARS-CoV-2 vaccines are mostly administered as boosters to individuals previously vaccinated with reference (Ref.) strain-based vaccines, a better understanding of their immunogenicity in this context is essential. Protein subunit vaccines have a well-established track record of safety. Herein, we assessed the ability of variant-specific protein subunit vaccine formulations to boost pre-existing Ref. strain-specific immune responses compared to boosting with a Ref. strain-specific formulation in young and aged female Balb/c mice. Methods: Following a priming vaccination series with Ref. spike protein adjuvanted with sulfated lactosyl archaeol (SLA) archaeosomes on days 0 and 21, immune responses were evaluated in young and aged female Balb/c mice. On day 91, mice received a third immunization with Ref., Beta, or Delta spike protein formulations, with or without SLA archaeosomes. Antibody titers, neutralization activity, and cellular immune responses were measured to assess the impact of the booster formulation. Results: Aged mice exhibited lower antibody titers throughout the study and a decline over time compared to young mice. After a third immunization, responses were boosted by all vaccine formulations (Ref., Beta, or Delta), with or without adjuvant. However, variant-specific antigen formulations did not overcome immune imprinting from the priming series or increase neutralization activity against the corresponding SARS-CoV-2 variants in either age group. Conclusions: Variant-specific protein subunit vaccines enhanced immune responses but did not overcome immune imprinting induced by the Ref. strain’s priming. The inclusion of SLA archaeosomes improved cellular immunity, supporting their potential role in optimizing booster vaccine performance, particularly in aged populations. Full article

Background/Objectives: Hypoxia promotes esophageal adenocarcinoma (EAC) aggressiveness through stabilization of hypoxia-inducible factor-1α (HIF-1α), which regulates pro-survival, pro-metastatic, and immunosuppressive pathways, including the ectoenzyme CD73 (NT5E). Although CD73 is a known hypoxia-responsive gene, its functional integration with HIF-1α signaling in EAC remains incompletely understood. This study aimed to define the relationship between HIF-1α and CD73 in EAC and to evaluate the therapeutic potential of their combined inhibition. Methods: Gene expression and survival analyses were performed using CCLE and TCGA-ESCA datasets. CD73 and HIF-1α expression were evaluated in EAC patient tissues by immunohistochemistry. EAC cell lines were subjected to hypoxic conditions with genetic or pharmacologic inhibition of HIF-1α and/or CD73. Cell viability, migration, angiogenesis, VEGF secretion, and purinergic metabolite levels were assessed using luminescence assays, Boyden chamber migration assays, endothelial tube formation assays, ELISA, and targeted LC-MS/MS, respectively. Results: NT5E expression was transcriptionally upregulated by HIF-1α under hypoxia and correlated with advanced disease stage and poor overall survival in EAC patients. While CD73 inhibition alone modestly reduced EAC cell viability, combined inhibition of HIF-1α and CD73 synergistically decreased tumor cell survival, particularly under hypoxic conditions, and significantly altered extracellular adenosine metabolism. Dual targeting further suppressed migration, reduced VEGF secretion, and impaired angiogenic signaling, indicating disruption of tumor microenvironmental pathways critical for metastasis and immune evasion. Conclusions: These findings identify CD73 as a direct hypoxia-responsive effector of HIF-1α in EAC and demonstrate that dual inhibition of HIF-1α and CD73 synergistically disrupts tumor cell survival and pro-metastatic signaling. This combinatorial strategy represents a mechanistically integrated therapeutic approach to overcome hypoxia-driven resistance in esophageal adenocarcinoma. Full article

Conventional cancer treatments often fail due to the immunosuppressive tumor microenvironment, immune tolerance, and chronic inflammation. Therefore, new therapeutic approaches are urgently needed. Cancer vaccines can stimulate natural killer cells and cytotoxic T-lymphocytes, and induce long-lasting memory responses that help overcome the immunosuppressive tumor microenvironment. Recent advances in nucleic acid, peptide, and dendritic cell-based vaccines have improved antigen delivery and immune activation, while combinations with immune checkpoint inhibitors and ablative therapies enhance therapeutic efficacy and durability. Preclinical and clinical studies targeting tumor-associated antigens have shown promising outcomes. With poor survival rates and limited treatment options, hepatocellular carcinoma (HCC) appears to be the most prevalent cause of cancer-related deaths worldwide. Advances in antigen discovery, vaccine delivery systems, and synergistic combination strategies are paving the way for more effective and durable immune responses. By integrating molecular insights with clinical innovation, cancer vaccines hold the potential not only to improve treatment outcomes but also to redefine long-term disease management and survival in HCC. Full article

Background: Chemotherapy, targeted therapy and radiotherapy are the cornerstones of cancer treatment. However, therapeutic resistance—not only to these classic modalities but also to novel therapeutics like immune checkpoint inhibitors (ICIs) and antibody-drug conjugates—remains a major hurdle. Resistance significantly limits efficacy and increases recurrence rates. A deep understanding of the molecular mechanisms driving this resistance is critical for developing personalized therapeutic strategies and improving patient outcomes. Recent Advances: Patient-derived cancer organoids have emerged as a powerful preclinical platform that faithfully recapitulates the genetic, phenotypic, and histological characteristics of original tumors. Consequently, PDOs are being widely utilized to evaluate drug responses, investigate resistance mechanisms, and discover novel therapeutic targets for a range of therapies. Limitations: While organoid models have been instrumental in studying resistance, significant limitations persist. First, standard organoid-only models lack key tumor microenvironment components, such as immune cells, limiting immunotherapy research. Second, there is a significant lack of research on acquired resistance, particularly in lung cancer. This gap is largely driven by the clinical infeasibility of rebiopsy in patients with progressive diseases. Third, the absence of standardized protocols for generating and validating resistance models hinders reproducibility and complicates clinical translation. Conclusions: This review summarizes recent advances in using organoid models to study resistance to chemotherapy, radiotherapy, and novel therapeutics (ICIs and ADCs). We emphasize the critical need for standardization in resistance organoid research. We also propose future directions to overcome existing challenges, including the integration of co-culture systems (to include the TME) and advanced technologies (e.g., scRNA-seq, Spatial Transcriptomics). Our specific focus is on advancing lung cancer resistance modeling to enable functional precision medicine. 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

Antibody-based therapeutics targeting tumor surface markers have transformed cancer treatment; however, their efficacy is frequently limited by tumor escape mechanisms such as antigen loss, phenotypic switching, and heterogeneous target expression. Beyond genetic or transcriptional changes, RNA alternative splicing (AS) has emerged as a central post-transcriptional mechanism driving antigenic diversity and immune escape. This review outlines how AS-generated isoforms remodel surface antigen structure and function across key therapeutic targets—including CD/19/CD20/CD22, EGFR/HER2, VEGF, and PD-1/PD-L1—thereby promoting resistance to monoclonal antibodies, antibody–drug conjugates, and immune checkpoint inhibitors. The aberrant activity of splicing regulators disrupts canonical exon selection, leading to altered receptor signaling or the secretion of soluble decoy isoforms that evade immune recognition. Emerging therapeutic strategies aim to counteract these processes through antisense oligonucleotide-mediated splicing correction, pharmacologic modulation of splicing regulators, and isoform-selective antibody or CAR-T designs. Collectively, understanding splicing-driven antigenic plasticity reveals an additional, dynamic layer of resistance regulation and provides a framework for developing RNA-informed precision antibody therapies designed to restore antigen expression, overcome immune escape, and enhance durable clinical responses. Full article