Search Results (91)

Cell surface immune checkpoint receptors are objects for therapeutic intervention to stimulate immune cell attack of cancers. Interference between the checking ectodomain (ECD) and the natural ligand lowers constitutive restraints exerted on immune cells. This approach assumes that immune cells can do more, that a checkpoint blocker will make immune cells more effective at killing cancer cells, and that checkpoint molecules might have limited physiological roles. These assumptions may be warranted, as in the case of checkpoint-blockers towards the programmed death-ligand 1 (PD-L1) ECD, where clinical outcomes are consistently good. However, this does not appear to be the case for the universally expressed CD47 ECD. Much effort has been directed at engineering molecules that bind to the CD47 ECD to increase T cell and macrophage killing of cancers. But a wealth of clinical data do not indicate strong signals, improved killing, or meaningful survival advantages. This suggests that the CD47 ECD is a subpar target for cancer therapy. Consideration of reasons accounting for the modest benefits realized by molecules that bind to the CD47 ECD in cancer, also known as Plan A, is provided. This is followed by thoughts on what might be done, known as plan B, to identify advantages within the CD47 ECD for modulating tolerance in autoimmune diseases. Full article

Magnesium (Mg²⁺) has garnered the attention of oncologists due to its wide range of biological functions and frequent use as a complementary or integrative agent. In this study, a concise narrative review of the complex relationships between Mg²⁺ and immunotherapy for human malignancies is presented, in addition to a possible future therapeutic scenario. Pertinent full-text articles were thoroughly examined, and the most relevant ones were selected for inclusion in this review. A significant body of preclinical studies highlights the role of Mg²⁺ in regulating immune function, particularly in cytotoxic effector cells, underscoring the importance of maintaining adequate Mg²⁺ homeostasis mainly when immune-modulating agents are used in clinical practice. Whether serum Mg²⁺ levels influence the clinical outcomes of cancer patients treated with immune checkpoint blocker treatment remains to be fully elucidated. However, over the last decade, an increasing amount of data suggests that maintaining normal or slightly elevated serum levels of Mg²⁺ may enhance the response to immune therapy and even improve survival outcomes. New potential modulators of the tumor microenvironment and response to immunotherapy, such as injectable gels and metal-based biomaterials, are discussed. Full article

Cancer-induced cardiac dysfunction has become a major clinical challenge as advances in cancer therapies continue to extend patient survival. Once regarded as a secondary concern, cardiotoxicity is now recognized as a leading contributor to morbidity and mortality among cancer patients and survivors. Its pathophysiology is multifactorial, involving systemic inflammation (e.g., TNF-α, IL-6), oxidative stress driven by reactive oxygen species (ROS), neurohormonal imbalances (e.g., angiotensin II, endothelin-1), and metabolic disturbances. These mechanisms collectively promote cardiomyocyte apoptosis, atrophy, mitochondrial dysfunction, and impaired cardiac output. Cardiac complications may arise directly from cancer itself or as adverse effects of oncologic therapies such as anthracyclines, trastuzumab, and immune checkpoint inhibitors. These agents have been linked to heart failure (HF), systolic dysfunction, and cardiac atrophy, often progressing insidiously and underscoring the importance of early detection and careful monitoring. Current preventive and therapeutic strategies include pharmacological interventions such as ACE inhibitors, beta-blockers, statins, dexrazoxane, and endothelin receptor antagonists like atrasentan. Emerging compounds, particularly Withaferin A (WFA), have shown potential through their anti-inflammatory and cardiac protective properties. In addition, antioxidants and lifestyle modifications may provide supplementary cardioprotective benefits, while interventional cardiology procedures are increasingly considered in selected patients. Despite encouraging progress, standardized treatment protocols and robust long-term outcome data remain limited. Given the heterogeneity of cancer types and cardiovascular responses, a personalized and multidisciplinary approach is essential. Continued research and close collaboration between oncologists, cardiologists, and basic scientists will be the key to advancing care, reducing treatment-related morbidity, and ensuring that improvements in cancer survival are matched by preservation of cardiovascular health. Full article

Background: Immune checkpoint inhibitor therapy in patients with lung cancer and metastatic melanoma is associated with exacerbation of autoimmune-related diseases. The efficacy of treatment targeting the programmed cell death receptor-1 (PD-1) checkpoint relies upon a feedback loop between interferon gamma (IFN-γ) and the interleukin-12 isoform, IL-12p40. Paradoxically, both cytokines and the anti-PD-1 antibody worsen psoriasis. We previously reported an immunomodulating peptide, designated IK14004, that inhibits progression of Lewis lung cancer in mice yet uncouples IFN-γ from IL-12p40 production in human immune cells. Methods: Immune cells obtained from healthy donors were exposed to IK14004 in vitro to further characterise the signalling pathways affected by this peptide. Using C57BL/6 immunocompetent mice, the effect of IK14004 was tested in models of lung melanoma and psoriatic skin. Results: Differential effects of IK14004 on the expression of IFN-α/β, the interleukin-15 (IL-15) receptor and signal transducers and activators of transcription were consistent with immune responses relevant to both cancer surveillance and immune tolerance. Moreover, both melanoma and psoriasis were inhibited by the peptide. Conclusions: Taken together, these findings suggest mechanisms underlying immune homeostasis that could be exploited in the setting of cancer and autoimmune pathologies. Peptide administered together with checkpoint blockers in relevant models of autoimmunity and cancer may offer an opportunity to gain further insight into how immune tolerance can be retained in patients receiving cancer immunotherapy. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most prevalent cancer worldwide. Despite intensive treatments, the prognosis is unfavorable. Recently, immunotherapy has emerged as a novel therapeutic strategy, and several immune-checkpoint blockade blockers provide clinical benefits to patients. However, the response rates of these antibodies are limited, and there is a pressing need to increase the efficacy of immunotherapy for HNSCC patients. Epigenetic treatment is emerging as a promising combination approach able to change immune-related gene signatures in tumors and potentially increase the efficacy of immunotherapy. In this study, we sought to elucidate further immune-related gene signatures altered through epigenetic treatment and explored whether epigenetic drugs can increase the efficacy of anti PD-L1 treatment in HNSCC. Methods: At first, we treated six HNSCC cell lines with 5-azacytidine and romidepsin and analyzed gene expression patterns by microarray and TaqMan arrays analysis. We then explored the therapeutic efficacy of epigenetic treatment with an anti PD-L1 antibody in a syngeneic mouse model. Results: Our microarray analysis revealed the differential expression of immune-related genes in cell lines treated with epigenetic drugs, as compared to untreated controls. Most importantly, these array analyses showed a significant change in the transcription of some immune related-and biologically relevant genes, such as HLA-DRA, HMOX1, IFI6, IL12A, IRF7, NFKB2, RPL3L, STAT1, STAT3, CSF1, CSF2, FAS, OASL, and PD-L1, after epigenetic treatment. Furthermore, the combination of epigenetic treatment with an anti PD-L1 antibody significantly suppressed tumor growth in a syngeneic mouse model. In vivo tumors treated with epigenetic drugs expressed higher STAT1, STAT3, and PD-L1 compared to untreated tumors. Increased PD-L1 expression is postulated to increase the efficacy of anti PD-L1 treatment. Conclusions: Our results highlight the importance of a combinational strategy employing both epigenetic and immunotherapy in HNSCC. Full article

The advent of personalized medicine and novel therapeutic strategies has transformed the treatment landscape of non-small cell lung cancer (NSCLC), significantly improving patient survival. However, only a minority of patients experience a durable benefit, as intrinsic or acquired resistance remains a major challenge. Understanding the complex mechanisms of resistance—linked to tumor biology, the tumor microenvironment (TME), and host factors—is crucial to overcoming these barriers. Recent innovations in diagnostics, including artificial intelligence and liquid biopsy, offer promising tools to refine therapeutic decisions. Machine Learning and Deep Learning provide predictive algorithms that enhance diagnostic accuracy and prognostic assessment. Techniques like single-cell RNA sequencing and pathomics offer deeper insights into the role of the TME. Liquid biopsy, as a minimally invasive method, enables real-time detection of circulating tumor components, facilitating the identification of predictive and prognostic biomarkers and illuminating tumor heterogeneity. These translational research advances are revolutionizing the understanding of cancer biology and are key to optimizing personalized treatment strategies. This review highlights emerging tools aimed at improving diagnostic and therapeutic precision in NSCLC, underscoring their role in decoding the interplay between tumor cells, the TME, and the host to ultimately improve patient outcomes. Full article

Background/Objectives: The nephrotoxicity of immune checkpoint inhibitors (ICIs) combined with proton pump inhibitors (PPIs) has been recognized but lacks a comprehensive analysis. We conducted an in-depth investigation of renal adverse events (rAEs) associated with ICIs and different acid-suppressing agents (ASAs)—including PPIs, histamine-2 receptor antagonists (H₂RAs), and potassium-competitive acid blockers (P-CABs)—using real-world data from the FDA’s Adverse Event Reporting System (FAERS). Methods: We analyzed rAE reports from the FAERS database covering Q1 2004 to Q1 2023. Disproportionality analysis was conducted to identify rAEs associated with ICI or ASA monotherapy or combination therapy. Univariate logistic regression was employed to explore influencing factors. Results: No eligible rAE reports were retrieved for H₂RAs and P-CABs. However, 6,775 reports in the ICI group, 54,055 reports in the PPI group, and 210 reports in the ICI–PPI combination therapy group were included in the final analysis. In PPI–ICI combination settings, tubulointerstitial nephritis had the highest reporting frequency and signal intensity; the overall risk of rAEs was significantly elevated compared to ICI or PPI monotherapy, with reporting odds ratios of 14. 65 (95% confidence interval [CI] 12.93–16.58) and 3.24 (95% CI 2.87–3.66), respectively; the median onset time was shortest at 21 days (interquartile range 5.5–135); and PD-1 monotherapy, omeprazole, and rabeprazole were associated with higher rAE risks. Conclusions: Our findings confirm that the combination of PPIs (but not other ASAs) with ICIs further increases the risk of various acute and chronic rAEs. Healthcare providers should exercise caution when managing patients on these therapies. Full article

Phosphoinositide 3-kinases (PI3Ks) signaling represents an important pathway regulating cell proliferation, survival, invasion, migration, and metabolism. Notably, PI3K/AKT/mTOR signaling is frequently dysregulated in the majority of malignancies. Among the class IA PI3Ks (PI3Kα/β/δ), emerging evidence has implicated that PI3Kδ is not only overexpressed in leukocytes but also in solid tumors, including prostate cancer. The critical role of PI3Kδ in tumorigenesis and in the creation of a suppressive tumor microenvironment, along with the recent finding of PI3Kδ splice isoforms in promoting tumor aggressiveness and resistance, further demonstrates the potential of developing novel PI3Kδ-targeted cancer therapies. In this review, we comprehensively describe the functional mechanisms underlying the PI3Kδ-driven tumor progression and immune regulation in prostate cancer diseases. Furthermore, the recent preclinical and clinical studies on the development of PI3Kδ-/PI3K-targeted inhibitors as single agents and in combination therapies (with chemotherapy, radiation, hormone therapy, or immunotherapy) are summarized. Finally, we discuss the potential novel therapies for improving the treatment efficacies, as well as the current limitations and challenges of PI3Kδ-based therapies for prostate cancer. Full article

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival. Full article

Secondary dilated cardiomyopathy (DCM) refers to left ventricular dilation and impaired systolic function arising from identifiable extrinsic causes, such as ischemia, hypertension, toxins, infections, systemic diseases, or metabolic disorders. Unlike primary DCM, which is predominantly genetic, secondary DCM represents a diverse spectrum of pathophysiological mechanisms linked to external insults on myocardial structure and function. The increasing prevalence of conditions such as alcohol use disorder, chemotherapy-induced cardiotoxicity, and viral myocarditis underscores the need for heightened awareness and early recognition of secondary DCM. A comprehensive analysis of clinical trial data and observational studies involving secondary dilative cardiomyopathy was conducted, with a focus on mortality, symptom relief, and major adverse events. A systematic literature review was performed using databases, including PubMed, Embase, and ClinicalTrials.gov, following PRISMA guidelines for study selection. Data were extracted on patient demographics, etiology of dilation, trial design, outcomes, and follow-up duration. Advances in diagnostic modalities have refined the ability to identify underlying causes of secondary DCM. For example, high-sensitivity troponin and cardiac magnetic resonance imaging are pivotal in diagnosing myocarditis and differentiating it from ischemic cardiomyopathy. Novel insights into toxin-induced cardiomyopathies, such as those related to anthracyclines and immune checkpoint inhibitors, have highlighted pathways of mitochondrial dysfunction and oxidative stress. Treatment strategies emphasize the management of the causing condition alongside standard heart failure therapies, including RAAS inhibitors and beta-blockers. Emerging therapies, such as myocardial recovery protocols in peripartum cardiomyopathy and immune-modulating treatments in myocarditis, are promising in reversing myocardial dysfunction. Secondary DCM encompasses a heterogeneous group of disorders that require a precise etiological diagnosis for effective management. Timely identification and treatment of the underlying cause, combined with optimized heart failure therapies, can significantly improve outcomes. Future research focuses on developing targeted therapies and exploring the role of biomarkers and precision medicine in tailoring treatment strategies for secondary DCM. Full article

Medicinal plants from the genus Saururus are commonly used to treat inflammatory pathologies. They contain numerous bioactive compounds, notably the polycyclic lignan sauchinone from the species Saururus chinensis. An in-depth analysis of benzoxanthenone lignans related to sauchinone, and the analogous products carpanone and polemannones, has been carried out. The review reports the product’s isolation, biosynthetic pathway, and chemical strategies to synthesize benzoxanthenones via liquid- and solid-phase syntheses. The metabolic and pharmacokinetic properties of sauchinone are discussed. At the pharmacological level, sauchinone is a potent blocker of the production of pro-inflammatory mediators, such as nitric oxide and prostaglandin E2, and an efficient antioxidant agent. The properties of sauchinone can be exploited to combat multiple pathologies, such as liver injuries, renal dysfunction, osteoarthritis, inflammatory bowel disease, ulcerative colitis, and cancers. The capacity of the natural product to inhibit tumor cell proliferation and to reduce migration/invasion of cancer cells and the development of metastases is underlined, together with the regulation of the epithelial-mesenchymal transition and immune checkpoints. Altogether, the review offers a complete survey of the chemical and biochemical properties of sauchinone-type benzoxanthenones. Full article

Human papillomavirus (HPV)-related lower genital cancers, including cervical cancer, anal squamous cell carcinoma (SCC), vaginal cancer, vulvar cancer, and penile cancer, pose a significant health burden, with approximately 45,000 new cases diagnosed annually. Current effective treatment modalities include chemoradiotherapy, systemic chemotherapy, and immune checkpoint inhibitors (ICIs). The tumor microenvironment in HPV-related cancers is characterized by immune evasion mechanisms, including the modulation of immune checkpoints such as PD-L1/PD-1. HPV oncoproteins E5, E6, and E7 play crucial roles in this process, altering the expression of immune inhibitory molecules and the recruitment of immune cells. ICIs, such as programmed cell death protein 1 (PD-1) inhibitors, have shown efficacy in enhancing the immune response against HPV-associated tumors by blocking proteins that allow cancer cells to evade immune surveillance. Recent studies have demonstrated that HPV-positive tumors exhibit a more favorable response to ICI-based therapies compared to HPV-negative tumors. The integration of ICIs into treatment regimens for HPV-related cancers has been supported by several clinical trials. The inclusion of ICIs in the treatment approach for HPV-related lower genital cancers presents a promising opportunity for improving patient outcomes. Ongoing research and clinical trials are advancing our understanding of the immune microenvironment and the therapeutic potential of immunotherapy for these cancers. Full article

Background/Objectives: microRNAs are small non-coding RNAs that regulate gene expression by inducing mRNA degradation or inhibiting translation. A growing body of evidence suggests that miRNAs may be utilized as anti-cancer therapeutics by targeting expression of key genes involved in cancerous transformation and progression. Renal cell cancer (RCC) is the most common kidney malignancy. The most efficient RCC treatments involve blockers of immune checkpoints, including antibodies targeting PD-L1 (Programmed Death Ligand 1). Interestingly, recent studies revealed the cross-kingdom horizontal transfer of plant miRNAs into mammalian cells, contributing to the modulation of gene expression by food ingestion. Here, we hypothesized that PD-L1 expression may be modulated by miRNAs originating from edible plants. Methods: To verify this hypothesis, we performed bioinformatic analysis to identify mes-miR395e from Manihot esculenta (cassava) as a promising candidate miRNA that could target PD-L1. To verify PD-L1 regulation mediated by the predicted plant miRNA, synthetic mes-miR395 mimics were transfected into cell lines derived from RCC tumors, followed by evaluation of PD-L1 expression using qPCR and Western blot. Results: Transfection of mes-miR395e mimics into RCC-derived cell lines confirmed that this miRNA decreases expression of PD-L1 in RCC cells at both mRNA and protein levels. Conclusions: This preliminary study shows the promise of plant miRNA as potential adjuvants supporting RCC treatment. Full article

Despite multimodal therapies, the treatment of glioblastoma remains challenging. In addition to the very complex mechanisms of cancer cells, including specialized phenotypes that enable them to proliferate, invade tissues, and evade immunosurveillance, they exhibit a pronounced resistance to chemo- and radiotherapy. More advanced tumors create a hypoxic environment that supports their proliferation and survival, while robust angiogenesis ensures a constant supply of nutrients. In GBM, these structures are very pronounced and contribute to the creation and maintenance of a highly immunosuppressive microenvironment that promotes tumor growth and immune escape. In addition, the high accumulation of immunosuppressive tumor-infiltrating leukocytes and other cells, the pronounced expression of immune checkpoint molecules, and the low mutational burden, i.e., the low number of neoantigens, are hallmarks of GBM and contribute to the challenge of therapeutic approaches. Here, we review a number of mechanisms that GBM exploits to support tumor growth and potential treatments. These include new chemotherapeutics, tumor treating fields, and small molecules, including compounds targeting angiogenesis or blockers of tyrosine kinases that inhibit tumor cell proliferation and survival. In addition, we focus on immunotherapies such as immune checkpoint blockade or cell therapies, in particular vaccination with dendritic cells and CAR-T cells, which can either kill GBM cells directly or bypass immunosuppression by modulating the tumor microenvironment or boosting the patient’s own immune response. Full article

Immunotherapy is an established and efficient treatment strategy for a variety of malignancies. It aims to boost the anticancer properties of one’s own immune system. Several immunotherapeutic options are available, but immune checkpoint blockers represent the most widely known and investigated. Anticancer vaccines represent an evolving area of immunotherapy that stimulate antigen-presenting cells, cytotoxic responses of CD8+ T cells, and the presence of memory T cells, among others. Over the years, different approaches for anticancer vaccines have been studied, such as mRNA and DNA vaccines, together with dendritic cell- and viral vector-based vaccines. Recently, an accumulating number of clinical studies have been performed to analyze the safety and potential efficacy of these agents. The aim of this review is to summarize recent advances regarding different types of therapeutic anticancer vaccines. Furthermore, it will discuss how recent advances in preclinical models can enhance clinical outcomes. Full article