Search Results (7,382)

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes. Full article

CD26 (dipeptidyl peptidase-4) is a marker of colorectal cancer stem cells with high metastatic potential and resistance to therapy. Although CD26 expression is known to be associated with tumor progression, its functional involvement in epithelial-mesenchymal transition (EMT) and metastasis remains to be fully elucidated. In this study, we aimed to investigate the effects of a monoclonal anti-CD26 antibody on EMT-related phenotypes and metastatic behavior in colorectal cancer cells. We evaluated changes in EMT markers by quantitative PCR and Western blotting, assessed cell motility and invasion using scratch wound-healing and Transwell assays, and examined metastatic potential in vivo using a splenic injection mouse model. Treatment with the anti-CD26 antibody significantly increased the expression of the epithelial marker E-cadherin and reduced levels of EMT-inducing transcription factors, including ZEB1, Twist1, and Snail1, at the mRNA and protein levels. Functional assays revealed that the antibody markedly inhibited cell migration and invasion in vitro without exerting cytotoxic effects. Furthermore, systemic administration of the anti-CD26 antibody significantly suppressed the formation of liver metastases in vivo. These findings suggest that CD26 may contribute to the regulation of EMT and metastatic behavior in colorectal cancer. Our data highlight the potential therapeutic utility of CD26-targeted antibody therapy for suppressing EMT-associated phenotypes and metastatic progression. Full article

Glioblastoma (GBM) is a highly aggressive brain tumor marked by invasive growth and therapy resistance. Tumor cells adapt to hostile conditions, such as hypoxia and nutrient deprivation, by activating survival mechanisms including autophagy and metabolic reprogramming. Among GBM-associated changes, hypersialylation, particularly, the aberrant expression of polysialic acid (PSA), has been linked to increased plasticity, motility, and immune evasion. PSA, a long α2,8-linked sialic acid polymer typically attached to the NCAM, is abundant in the embryonic brain and re-expressed in cancers, correlating with poor prognosis. Here, we investigated how PSA expression was regulated in GBM cells under nutrient-limiting conditions. Serum starvation induced a marked increase in PSA-NCAM, driven by upregulation of the polysialyltransferase ST8SiaIV and an autophagy-dependent recycling of sialic acids from degraded glycoproteins. Inhibition of autophagy or sialidases impaired PSA induction, and PSA regulation appeared dependent on p53 function. Immunohistochemical analysis of GBM tissues revealed co-localization of PSA and LC3, particularly around necrotic regions. In conclusion, we identified a novel mechanism by which GBM cells sustain PSA-NCAM expression via autophagy-mediated sialic acid recycling under nutrient stress. This pathway may enhance cell migration, immune escape, and stem-like properties, offering a potential therapeutic target in GBM. Full article

Liquid biopsy has emerged as a valuable tool for the detection and monitoring of colorectal cancer (CRC), providing minimally invasive insights into tumor biology through circulating biomarkers such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Additional biomarkers, including tumor-educated platelets (TEPs) and exosomal RNAs, offer further potential for early detection and prognostic role, although ongoing clinical validation is still needed. This review summarizes the current evidence on the diagnostic, prognostic, and predictive capabilities of liquid biopsy in both metastatic and non-metastatic CRC. In the non-metastatic setting, liquid biopsy is gaining traction in early detection through screening and in identifying minimal residual disease (MRD), potentially guiding adjuvant treatment and reducing overtreatment. In contrast, liquid biopsy is more established in metastatic CRC for monitoring treatment responses, clonal evolution, and mechanisms of resistance. The integration of ctDNA-guided treatment algorithms into clinical practice could optimize therapeutic strategies and minimize unnecessary interventions. Despite promising advances, challenges remain in assay standardization, early-stage sensitivity, and the integration of multi-omic data for comprehensive tumor profiling. Future efforts should focus on enhancing the sensitivity of liquid biopsy platforms, validating emerging biomarkers, and expanding multi-omic approaches to support more targeted and personalized treatment strategies across CRC stages. Full article

Reactive oxygen species (ROS) are often seen solely as harmful byproducts of oxidative metabolism, yet evidence reveals their paradoxical roles in both promoting and inhibiting cancer progression. Despite advances, precise context-dependent mechanisms by which ROS modulate oncogenic signaling, therapeutic response, and tumor microenvironment dynamics remain unclear. Specifically, the spatial and temporal aspects of ROS regulation (i.e., the distinct effects of mitochondrial versus cytosolic ROS on the PI3K/Akt and NF-κB pathways, and the differential cellular outcomes driven by acute versus chronic ROS exposure) have been underexplored. Additionally, the specific contributions of ROS-generating enzymes, like NOX isoforms and xanthine oxidase, to tumor microenvironment remodeling and immune modulation remain poorly understood. This review synthesizes current findings with a focus on these critical gaps, offering novel mechanistic insights into the dualistic nature of ROS in cancer biology. By systematically integrating data on ROS source-specific functions and redox-sensitive signaling pathways, the complex interplay between ROS concentration, localization, and persistence is elucidated, revealing how these factors dictate the paradoxical support of tumor progression or induction of cancer cell death. Particular attention is given to antioxidant mechanisms, including NRF2-mediated responses, that may undermine the efficacy of ROS-targeted therapies. Recent breakthroughs in redox biosensors (i.e., redox-sensitive fluorescent proteins, HyPer variants, and peroxiredoxin–FRET constructs) enable precise, real-time ROS imaging across subcellular compartments. Translational advances, including redox-modulating drugs and synthetic lethality strategies targeting glutathione or NADPH dependencies, further highlight actionable vulnerabilities. This refined understanding advances the field by highlighting context-specific vulnerabilities in tumor redox biology and guiding more precise therapeutic strategies. Continued research on redox-regulated signaling and its interplay with inflammation and therapy resistance is essential to unravel ROS dynamics in tumors and develop targeted, context-specific interventions harnessing their dual roles. Full article

The secondary metabolites of the fungus Penicillium thymicola, fumiquinazolines F and G, have antibacterial and antifungal characteristics; however, their potential anti-tumor action against human cancer cells remains unknown. The goal of our study was to determine the biological efficacy of fumiquinazolines F and G on breast and prostate cancer cells. Cancer cell proliferation and migration were monitored in real time using xCELLigence technology and flow cytometry. Alterations in mRNA and protein expression were assessed by RT-qPCR, ELISA, and Western blotting. Our data indicate that fumiquinazolines F and G are more effective in inhibiting breast cancer cell proliferation than prostate cancer cells. Fumiquinazoline F is active against both hormone-dependent epithelial MCF-7 (IC₅₀ 48 μM) and hormone-resistant triple-negative mesenchymal MDA-MB-231 breast cancer cells (IC₅₀ 54.1 μM). The metabolite has low cytotoxicity but slows cell cycle progression. In fumiquinazoline F-treated MDA-MB-231 cells, the levels of proteins implicated in epithelial–mesenchymal transition (EMT) (such as E-cadherin, vimentin, and CD44) fluctuate, resulting in a decrease in cell migratory rate and adhesion to a hyaluronic acid-coated substrate. Thus, fumiquinazolines F and G exhibit anticancer activity by inhibiting EMT, cell proliferation, and migration, hence reverting malignant cells to a less pathogenic phenotype. The compound’s multi-target anticancer profile underscores its potential for further exploration of novel EMT-regulating pathways. Full article

Chimeric antigen receptor (CAR)-T immunotherapy has revolutionized the management of patients with relapsed/refractory B-cell hematological malignancies. There is emerging evidence that CAR-engineered cells—not only T cells, but also natural killers and macrophages—might have a crucial role in the treatment of autoimmune disorders and solid tumors. Moreover, given the burden of chronic infectious diseases, the mortality and morbidity of infections in immunocompromised individuals, and the development of multidrug-resistant pathogens, including bacteria, fungi, and mycobacteria, a need for novel and personalized therapeutics in this field is emerging. To this end, the development of CAR cells for the management of chronic infections has been reported. In this literature review, we summarize the ongoing clinical and pre-clinical data about CAR cell products in the field of infectious diseases. Currently, clinical studies on CAR immunotherapy for infections mainly concern human immunodeficiency virus infection treatment, and data regarding other infections largely originate from preclinical in vitro and in vivo models. In the era of personalized medicine, effective and safe therapies for the management of chronic infections and infectious complications in immunocompromised patients are crucial. Full article

Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAF^V600E mutation, for which vemurafenib, a selective BRAF^V600E inhibitor, is approved. Despite initial clinical benefits, vemurafenib often leads to drug resistance and relapse, highlighting the need for improved therapeutic strategies. Objectives, methods: In this study, we designed, synthesized, and characterized five novel vemurafenib analogs—RF-86A, RF-87A, RF-94A, RF-94B, and RF-96B—with the aim of enhancing anti-proliferative and anti-metastatic effects against human melanoma cells. Results: All compounds induced apoptosis in BRAF^V600E-mutated A375 cells, with RF-86A displaying the lowest IC₅₀ value among the series, comparable to that of vemurafenib. Moreover, RF-86A exhibited the highest selectivity index, as determined using HEK293T cells as a non-tumorigenic control. Additionally, migration assays and gelatin zymography demonstrated that the analogs, unlike vemurafenib, significantly inhibited matrix metalloproteinases MMP-2 and MMP-9, key enzymes involved in tumor invasion and metastasis. Conclusions: These findings suggest that structural modifications to the vemurafenib scaffold may improve therapeutic efficacy and offer a promising strategy to overcome acquired resistance. Full article

Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers. Full article

Background/Objectives: Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths worldwide, with its incidence rising each year. Despite its relatively low incidence, the aggressiveness of pancreatic cancer results in high mortality, with only 12% of patients surviving five years post-diagnosis. Surgical resection remains the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage. The goal of this work is to identify vulnerabilities that can affect the efficacy of treatments and improve the efficacy of therapy. Methods: MAP17 overexpression in pancreatic cancer cell lines, RT-qPCR analysis, xenografts, in vitro and in vivo treatments, analysis of data from pancreatic tumors in transcriptomic patient databases. Results: We studied the prognostic and predictive value of MAP17 (PDZK1IP1) expression in pancreatic cancer, and we found that high MAP17 mRNA expression was associated with poor prognosis. In addition, single-cell analysis revealed that high MAP17 expression was present only in tumor cells. We investigated whether the response to various antitumor agents depended on MAP17 expression. In 2D culture, MAP17-expressing pancreatic cancer cells responded better to gemcitabine and 5-fluorouracil. However, in vivo xenograft tumors with MAP17 expression showed resistance to all treatments. Additionally, MAP17-expressing cells had a high NAD pool, which seems to be effectively depleted in vivo by NAMPT inhibitors, the primary enzyme for NAD biosynthesis. Conclusions: Our findings suggest that MAP17 expression could enhance the prognostic stratification of pancreatic cancer patients. Moreover, the coadministration of NAMPT inhibitors with current treatments may sensitize tumors with high MAP17 expression to chemotherapy and improve the efficacy of chemotherapy. Full article

Immunotherapy has revolutionized cancer treatment. Despite its success across various malignancies, a significant proportion of patients either fail to respond (primary resistance) or relapse after an initial response (acquired resistance). This review explores the different mechanisms underlying resistance to immunotherapy, including tumor-intrinsic factors such as loss of antigen presentation, genetic, and epigenetic mutations. It also examines tumor-extrinsic contributors, such as immunosuppressive cells in the tumor microenvironment, checkpoint molecule upregulation, and microbiome influences. A comprehensive understanding of resistance mechanisms is essential for improving patient selection, developing combination therapies, and ultimately enhancing the efficacy and durability of immunotherapeutic interventions. Full article

Cancer and infectious diseases are major causes of global morbidity and mortality stressing the need to find novel drugs with promising dual anticancer and antimicrobial efficacy. Gold complexes have been studied for the past years due to their anticancer properties, with a few of them displaying antimicrobial properties, which support their pharmacological interest. Within this scope, we investigated six gold bisdithiolate complexes [Au (bdt)₂]⁻ (1), [Au (dcbdt)₂]⁻ (2), [Au (3-cbdt)₂]⁻ (3), [Au (4-cbdt)₂]⁻ (4), [Au (pdt)₂]⁻ (5) and [Au (dcdmp)₂]⁻ (6), and) against the ovarian cancer cell lines A2780 and A2780cisR, the Gram-positive bacteria Staphylococcus aureus Newman, the Gram-negative bacteria Escherichia coli ATCC25922 and Burkholderia contaminans IST408, and the pathogenic yeasts Candida glabrata CBS138 and Candida albicans SC5134. Complexes 2 and 6, with ligands containing aromatic pyrazine or phenyl rings, substituted with two cyanonitrile groups, showed after 24 h of incubation high anticancer activities against A2780 ovarian cancer cells (IC₅₀~5 µM), being also able to overcome cisplatin resistance in A2780cisR cells. Both complexes induced the formation of ROS, activated caspase-3/7, and induced necrosis (LDH release) in a dose-dependent way, in a greater extent in the case of 6. Among the bacterial and fungal strains tested, only complex 6 presented antimicrobial activity against S. aureus Newman, indicating that this complex is a potential novel anticancer and antibacterial agent. These results delve into the structure-activity relationship of the complexes, considering molecular alterations such as replacing a phenyl group for a pyrazine group, and the inclusion of one or two cyanonitrile appendage groups, and their effects on biological activity. Overall, both complexes were found to be promising leads for the development of future anticancer drugs against low sensitive or cisplatin resistant tumors. Full article

Background/Objectives: Medulloblastoma is the most common malignant brain tumor in children and comprises four molecular subtypes—WNT, SHH, Group 3, and Group 4—each with distinct genetic, epigenetic, and metabolic features. Increasing evidence highlights the critical role of metabolic reprogramming and epigenetic alterations in driving tumor progression, therapy resistance, and clinical outcomes. This review aims to explore the interplay between metabolic and epigenetic mechanisms in medulloblastoma, with a focus on their functional roles and therapeutic implications. Methods: A comprehensive literature review was conducted using PubMed and relevant databases, focusing on recent studies examining metabolic pathways and epigenetic regulation in medulloblastoma subtypes. Particular attention was given to experimental findings from in vitro and in vivo models, as well as emerging preclinical therapeutic strategies targeting these pathways. Results: Medulloblastoma exhibits metabolic adaptations such as increased glycolysis, lipid biosynthesis, and altered amino acid metabolism. These changes support rapid cell proliferation and interact with the tumor microenvironment. Concurrently, epigenetic mechanisms—including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation—contribute to tumor aggressiveness and treatment resistance. Notably, metabolic intermediates often serve as cofactors for epigenetic enzymes, creating feedback loops that reinforce oncogenic states. Preclinical studies suggest that targeting metabolic vulnerabilities or epigenetic regulators—and particularly their combination—can suppress tumor growth and overcome resistance mechanisms. Conclusions: The metabolic–epigenetic crosstalk in medulloblastoma represents a promising area for therapeutic innovation. Understanding subtype-specific dependencies and integrating biomarkers for patient stratification could facilitate the development of precision medicine approaches that improve outcomes and reduce long-term treatment-related toxicity in pediatric patients. Full article

Conventional immunotherapy, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cells, has revolutionized cancer therapy over the past decade. Yet, the efficacy of these therapies is limited by tumor resistance, antigen escape mechanisms, poor persistence, and T-cell exhaustion, particularly in the treatment of solid tumors. The emergence of unconventional immunotherapies offers novel opportunities by leveraging diverse immune cell subsets and synthetic biologics. This review explores various immunotherapy platforms, including gamma delta T cells, invariant natural killer T cells, mucosal-associated invariant T cells, engineered regulatory T cells, and universal CAR platforms. Additionally, it expands on biologics, including bispecific and multispecific antibodies, cytokine fusions, agonists, and oncolytic viruses, showcasing their potential for modular engineering and off-the-shelf applicability. Distinct features of unconventional platforms include independence from the major histocompatibility complex (MHC), tissue-homing capabilities, stress ligand sensing, and the ability to bridge adaptive and innate immunity. Their compatibility with engineering approaches highlights their potential as scalable, efficient, and cost-effective therapies. To overcome translational challenges such as functional heterogeneity, immune exhaustion, tumor microenvironment-mediated suppression, and limited persistence, novel strategies will be discussed, including metabolic and epigenetic reprogramming, immune cloaking, gene editing, and the utilization of artificial intelligence for patient stratification. Ultimately, unconventional immunotherapies extend the therapeutic horizon of cancer immunotherapy by breaking barriers in solid tumor treatment and increasing accessibility. Continued investments in research for mechanistic insights and scalable manufacturing are key to unlocking their full clinical potential. Full article

Carboxypeptidase A4 (CPA4) is an exopeptidase that cleaves peptide bonds at the C-terminal domain within peptides and proteins. It preferentially cleaves peptides with terminal aromatic or branched chain amino acid residues such as phenylalanine, tryptophan, or leucine. CPA4 was first discovered in prostate cancer cells, but it is now known to be expressed in various tissues throughout the body. Its physiologic expression is governed by latexin, a noncompetitive endogenous inhibitor of CPA4. Nevertheless, the overexpression of CPA4 has been associated with the progression and aggressiveness of many malignancies, including prostate, pancreatic, breast and lung cancer, to name a few. CPA4’s role in cancer has been attributed to its disruption of many cellular signaling pathways, e.g., PI3K-AKT-mTOR, STAT3-ERK, AKT-cMyc, GPCR, and estrogen signaling. The dysregulation of these pathways by CPA4 could be responsible for inducing epithelial--mesenchymal transition (EMT), tumor invasion and drug resistance. Although CPA4 has been found to regulate cancer aggressiveness and poor prognosis, no comprehensive review summarizing the role of CPA4 in cancer is available so far. In this review, we provide a brief description of peptidases, their classification, history of CPA4, mechanism of action of CPA4 as a peptidase, its expression in various tissues, including cancers, its role in various tumor types, the associated molecular pathways and cellular processes. We further discuss the limitations of current literature linking CPA4 to cancers and challenges that prevent using CPA4 as a biomarker for cancer aggressiveness and predicting drug response and highlight a number of future strategies that can help to overcome the limitations. Full article