Search Results (1,526)

Copper (Cu) is an essential element required by all living cells, where it supports critical enzymatic and signaling functions. In cancer, this balance is often disrupted, creating vulnerabilities that can be therapeutically exploited. Changes in Cu availability have been shown to influence key immunoregulatory pathways, including those involved in inflammation, cell death, and immune evasion. Notably, Cu can drive expression of programmed death ligand 1 (PD-L1), contributing to immunosuppression, while also promoting immunogenic cell death, which stimulates adaptive immune responses. These dual effects highlight the complexity and therapeutic potential of Cu-based interventions, particularly in the context of immune modulation and toxicity. This review argues that Cu-based nanomedicines can selectively deliver high concentrations of bioactive Cu to tumor cells, inducing cell death and triggering adaptive immune responses. We summarize current knowledge on Cu’s roles in cancer and immunity, emphasizing recent insights into how these intersect through Cu-mediated modulation of anticancer immune pathways. Finally, we explore the clinical potential of Cu-based nanomedicines to convert immunologically “cold” tumors into “hot” ones, thereby improving responses to immunotherapy. Realizing this potential will depend on the thoughtful integration of Cu delivery approaches with existing immunotherapeutic strategies. Full article

Background/Objectives: Immunotherapy has improved outcomes for selected patients with advanced non-small-cell lung cancer (NSCLC), yet the predictive value of individual biomarkers such as PD-L1 remains limited. Systemic inflammatory indices derived from routine blood tests may complement molecular and immunohistochemical features, offering a broader view of host–tumor immunobiology. Methods: We conducted a retrospective study of 298 patients with stage IIIB–IV NSCLC treated with immune checkpoint inhibitors (ICIs) at a tertiary oncology center between 2022 and 2024. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune–inflammation index (SII) were collected alongside PD-L1 expression and molecular alterations (EGFR, KRAS, ALK, TP53). Patients were stratified into inflammatory–molecular clusters integrating these parameters. Associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan–Meier and multivariate Cox analyses. Results: Four distinct inflammatory–molecular clusters demonstrated significantly different outcomes (p < 0.001). Patients with low NLR and high PD-L1 expression (Cluster A) showed the highest ORR (41%), longest median PFS (13.0 months), and OS (22.5 months). The EGFR/ALK-driven, inflammation-dominant cluster (Cluster C) exhibited poor response (ORR 7%) and shortest survival (PFS 4.3 months). High NLR (HR 2.12), PD-L1 < 1% (HR 1.91), and EGFR mutation (HR 2.36) independently predicted shorter PFS. A combined model incorporating NLR, PD-L1, and molecular status outperformed individual biomarkers (AUC 0.82). Conclusions: Integrating systemic inflammatory indices with PD-L1 expression and molecular alterations identifies clinically meaningful NSCLC subgroups with distinct immunotherapy outcomes. This multidimensional approach improves prediction of ICI response and may enhance real-world patient stratification, particularly in settings with limited access to extended molecular profiling. Full article

Tuberculosis (TB) remains a leading infectious killer, increasingly complicated by multidrug-resistant (MDR) and extensively drug-resistant (XDR) disease; current regimens, although effective, are prolonged, toxic, and often fail to reach intracellular bacilli in heterogeneous lung lesions. This narrative review synthesizes how next-generation antimycobacterial strategies can be translated “from molecule to patient” by coupling potent therapeutics with delivery platforms tailored to the lesion microenvironment. We survey emerging small-molecule classes, including decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) inhibitors, mycobacterial membrane protein large 3 (MmpL3) inhibitors, and respiratory chain blockers, alongside optimized uses of established agents and host-directed therapies (HDTs). These are mapped to inhalable and nanocarrier systems that improve intralesional exposure, macrophage uptake, and targeted release while reducing systemic toxicity. Particular emphasis is placed on pulmonary dry powder inhalers (DPIs) and aerosols for direct lung targeting, stimuli-responsive carriers that trigger release through pH, redox, or enzymatic cues, and long-acting depots or implants that shift daily dosing to monthly or quarterly schedules to enhance adherence, safety, and access. We also outline translational enablers, including model-informed pharmacokinetic/pharmacodynamic (PK/PD) integration, device formulation co-design, manufacturability, regulatory quality frameworks, and patient-centered implementation. Overall, aligning stronger drugs with smart delivery platforms offers a practical pathway to shorter, safer, and more easily completed TB therapy, improving both individual outcomes and public health impact. Full article

Background: Mediastinal gray zone lymphoma (MGZL) is a rare B-cell lymphoma characterized by overlapping clinicopathologic and molecular features of primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL). Under current WHO-HEMA5 and International Consensus Classification (ICC) frameworks, MGZL is restricted to EBV-negative lymphomas arising in the mediastinum. Methods: This review summarizes current evidence on epidemiology, clinical presentation, pathology, molecular characteristics, diagnostic challenges, and therapeutic approaches to MGZL, with data derived from retrospective series, limited prospective cohorts, and recent molecular studies. Results: MGZL predominantly affects young adults and commonly presents with bulky mediastinal disease. Diagnosis is challenging due to transitional morphology, pleomorphic Reed–Sternberg-like cells, and variable expression of B-cell and activation markers. Molecular studies demonstrate shared alterations with PMBL and CHL, including 9p24.1 (JAK2/PD-L1/PD-L2) gains, while additional reported features such as HOXA5 hypomethylation and MYC copy number gains support its biological distinctiveness, although evidence remains limited. Frontline treatment commonly involves intensive chemoimmunotherapy regimens such as DA-EPOCH-R; however, outcomes remain inferior to PMBL and CHL, with 5-year overall survival rates of approximately 40–60%. Relapsed or refractory disease frequently requires salvage chemotherapy and autologous stem cell transplantation. Immune-based therapies, including brentuximab vedotin and PD-1 inhibitors, have shown promising activity, particularly in combination. Conclusions: MGZL remains a diagnostically challenging and therapeutically complex lymphoma with inferior outcomes compared with related mediastinal lymphomas. Advances in molecular profiling and immunotherapy offer promising avenues toward more personalized treatment; however, prospective clinical trials and international collaboration are urgently needed to establish evidence-based management strategies for this rare entity. Full article

Background: Durvalumab, a PD-L1 inhibitor used as consolidation therapy after chemoradiation in unresectable stage III non–small cell lung cancer (NSCLC), can induce immune-related adverse events, among which immune-mediated pneumonitis represents one of the most severe. Differentiating checkpoint inhibitor pneumonitis (CIP) from infectious pneumonia is challenging due to overlapping clinical and radiologic findings. Case presentation: We describe a 67-year-old woman with stage III lung adenocarcinoma treated with chemotherapy, radiotherapy, and durvalumab, who presented with progressive dyspnea and extensive bilateral ground-glass opacities on CT imaging. Laboratory tests revealed leukopenia and elevated inflammatory markers. Despite broad-spectrum antibiotic and antiviral therapy, her condition worsened, requiring high-flow nasal cannula oxygen therapy. Multiplex molecular testing on sputum identified human metapneumovirus (HMPV), while blood cultures and urinary antigens for Streptococcus pneumoniae and Legionella pneumophila were negative. A pulmonology consultation raised suspicion for severe durvalumab-induced pneumonitis exacerbated by viral infection. High-dose methylprednisolone (2 mg/kg/day) followed by a four-week taper led to gradual clinical and radiologic resolution. Durvalumab was permanently discontinued. Discussion: To our knowledge, this is the first reported case of HMPV-associated pneumonitis in a patient receiving durvalumab. This case highlights the potential synergistic interplay between viral infection and immune checkpoint blockade, resulting in severe lung injury. Comprehensive microbiologic evaluation, including molecular diagnostics, is essential to guide therapy and distinguish infectious from immune-mediated causes. Conclusions: Early recognition of mixed infectious and immune-mediated pneumonitis, and timely corticosteroid therapy are critical to achieving favorable outcomes and preventing irreversible pulmonary damage. 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

The microbiota–gut–brain axis (MGBA) comprises a complex bidirectional communication network integrating neural, immune, metabolic, and endocrine pathways. Dopamine, traditionally viewed as a central neurotransmitter, also plays essential roles in the gastrointestinal (GI) tract, where it regulates motility, secretion, barrier homeostasis, and mucosal immunity. Growing evidence indicates that the gut microbiota significantly contributes to intestinal dopamine metabolism through specialized enzymatic pathways, particularly tyrosine decarboxylase in Enterococcus species and catechol dehydroxylase in Eggerthella species. These microbial reactions compete with host processes, alter dopaminergic tone, and degrade orally administered levodopa (L-DOPA), providing a mechanistic explanation for the variability in treatment response in Parkinson’s disease (PD). Beyond PD, microbially mediated alterations in dopaminergic signaling have been implicated in mood disorders, neurodevelopmental conditions, metabolic dysfunction, and immune-mediated diseases. This review synthesizes current mechanistic and translational evidence on the dopamine–microbiota interface, outlines microbial pathways shaping dopaminergic activity, and highlights therapeutic opportunities including microbiota modulation, dietary strategies, fecal microbiota transplantation, and targeted inhibitors of microbial dopamine metabolism. Understanding this interface offers a foundation for developing personalized approaches in neurogastroenterology and neuromodulatory therapies. Full article

Background and Objectives: Urothelial carcinoma (UC) is one of the most prevalent and lethal cancers worldwide. Identifying and understanding the factors that influence treatment outcome is essential for improving therapeutic effectiveness and predicting patient response. The objective of this review is to estimate how clinical, biochemical, molecular and therapeutic factors impact the prognosis of patients with advanced urothelial carcinoma (aUC) and metastatic urothelial carcinoma (mUC) treated with immune checkpoint inhibitors (ICIs). Methods: A review was performed using PubMed, Scopus and Web of Science databases. All articles were published from 2013 to 2025 focusing on prognostic factors in locally advanced and metastatic urothelial carcinoma treated with ICIs. Results: Clinical prognostic factors for patients treated with ICIs include poor Eastern Cooperative Oncology Group (ECOG) performance status and the presence of liver or bone metastases, both associated with poor outcomes. Low hemoglobin levels and several biochemical markers, such as high neutrophil-to-lymphocyte ratio (NLR), elevated systemic immune-inflammation index (SII) and low serum sodium are also associated with reduced survival. Programmed cell death-ligand 1 (PD-L1) expression shows predictive relevance for ICI response. Concomitant use of antibiotics or proton pump inhibitors (PPIs) may diminish immunotherapy effectiveness. Additionally, sarcopenia and high lactate dehydrogenase (LDH) levels correlate with poorer clinical outcomes. Conclusions: Prognostic outcomes in aUC and mUC are influenced by a complex interaction of clinical, biochemical and molecular factors. Integrative prognostic models are essential to the guidance of personalized immunotherapeutic strategies and the improvement of patient outcomes in aUC and mUC. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) show durable efficacy in tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), yet clinical responses remain heterogeneous. This study aimed to define immune subgroups within dMMR/MSI-H tumors and develop a reproducible transcriptomic signature predictive of ICI response. Methods: Four MSI-H-enriched cancer types (UCEC, COAD, READ, STAD) from The Cancer Genome Atlas were analyzed. Tumors were stratified by immune cell infiltration (MCP-counter immune composite score) and T-cell-inflamed gene expression profiles (GEP score). Integrating these two axes defined four immune subgroups. Differential expression, random forest feature selection, and pathway enrichment were performed to identify immune programs. A 20-gene immune signature representing the most immune-active subgroup was developed and validated across TCGA, GEO (GSE39582), and IMvigor210 cohorts. Results: Among the four subgroups, the most immune-active group showed strong activation of interferon signaling, antigen presentation, and T-cell-mediated pathways. The 20-gene signature—including CD74, STAT1, TAP1, and HLA-class genes—achieved high reproducibility (mean AUC = 0.95 ± 0.02; accuracy ≈ 89%). In the IMvigor210 cohort, this signature identified tumors with higher PD-L1 blockade response (55.6% vs. 32.8%, p = 0.034) and improved survival trends in the TMB-high subset. Conclusions: The proposed 20-gene signature quantitatively captures immune heterogeneity in dMMR/MSI-H tumors and serves as a practical, interpretable biomarker to identify true ICI responders and guide precision immunotherapy. Full article

Diffuse pleural mesothelioma (PM) is a rare thoracic malignancy with historically limited treatment options and poor outcomes. Despite the recent breakthrough of dual immune checkpoint blockade (ICB)—notably the combination of anti-PD-1 and anti-CTLA-4 therapies—clinical responses remain variable and overall survival gains modest. Consequently, there is an urgent need for multidimensional biomarkers and adaptive trial designs to unravel the complexity of PM immune biology. This review provides a comprehensive overview of current evidence on how histological subtypes (epithelioid vs. non-epithelioid) influence ICB efficacy, highlighting distinct genetic landscapes (e.g., BAP1, CDKN2A, NF2 mutations) and tumor microenvironment (TME) features, including immune infiltration patterns and PD-L1 or VISTA expression, that underlie differential responses. We further examine intrinsic tumor factors—such as mutational burden and checkpoint ligand expression—and extrinsic determinants, including immune cell composition, stromal architecture, patient immune status, and microbiota, as modulators of immunotherapy outcomes. We also discuss the rationale behind emerging strategies designed to enhance ICB efficacy, currently under clinical evaluation. These include combination regimens with chemotherapy, radiotherapy, surgery, epigenetic modulators, anti-angiogenic agents, and novel immunotherapies such as next-generation checkpoint inhibitors (LAG-3, VISTA), immune-suppressive cell–targeting agents, vaccines, cell-based therapies, and oncolytic viruses. Collectively, these advancements underscore the importance of integrating histological classification with molecular and microenvironmental profiling to refine patient selection and guide the development of combination strategies aimed at transforming “cold” mesotheliomas into “hot,” immune-responsive tumors, thereby enhancing the efficacy of ICB. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) orchestrates redox balance, metabolism, and cellular stress responses, acting as both a tumor suppressor and promoter depending on the disease stage. In advanced cancers, persistent NRF2 activation—through KEAP1/NFE2L2 mutations or oxidative adaptation—drives epithelial-to-mesenchymal transition, metabolic reprogramming, and immune evasion, promoting tumor invasion (T) and metastasis (M). Recent pharmacologic efforts seek to exploit this duality. NRF2 inhibitors such as brusatol, halofuginone, and ML385 suppress NRF2 transcriptional activity or disrupt DNA binding, reducing motility, invasion, and metastatic dissemination in preclinical models. In contrast, NRF2 activators, such as bardoxolone methyl (CDDO-Me), sulforaphane, and dimethyl fumarate, exhibit chemopreventive effects by enhancing detoxification and mitigating oxidative DNA damage during early tumorigenesis. Furthermore, metabolic interventions, such as glutaminase or G6PD inhibitors, target NRF2-driven anabolic and antioxidant pathways essential for metastatic fitness. Therefore, understanding the temporal and contextual effects of NRF2 signaling is crucial for therapeutic design. The aim of this review is to examine how pharmacological modulation of NRF2 influences the invasive and metastatic dimensions of tumor progression, in addition to discussing its potential integration into TNM-based prognostic and treatment frameworks. Full article

Carborane is considered a three-dimensional mimetic of phenyl rings in medicinal chemistry. BMS-202 is a potent PD-L1 inhibitor that can block the PD-L1/PD-1 interaction and restore the immune response to cancer cells. Herein, we replaced the terminal phenyl group of BMS-202 with carborane and prepared its carboranyl BMS-202 analogues. The results showed a loss of PD-L1 binding affinity due to the bulky size of carborane, suggesting that carborane cannot serve as a phenyl ring mimetic in certain cases. Docking study demonstrated that the narrow binding pocket of PD-L1 could not hold the bulky carborane, resulting in loss of its activity. Compounds 1a and 1b exhibited anti-proliferative activities on a broad scope of cancer cell lines. Further studies indicate that compound 1a can induce cell apoptosis and lead to G1 cell cycle phase arrest. The boron biodistribution study of compound 1a revealed that the brain/blood uptake ratio was 0.60 ± 0.08, exhibiting a good blood-brain penetration capability. Full article

The limited efficacy of cytotoxic chemotherapy in the context of gastric cancer treatment is largely driven by profound molecular and biological heterogeneity. In contrast, the development of antibody-mediated therapies has ushered in a new era of precision oncology by enabling selective molecular targeting and immune modulation. This review includes a comprehensive overview of the evolution of antibody-based therapeutics in gastric cancer, highlighting early breakthroughs, subsequent setbacks, and recent advances that have reshaped the treatment landscape. We summarize the current standard regimens targeting HER2, VEGFR2, PD-1/PD-L1, and CLDN18.2 and examine pivotal clinical trials evaluating monoclonal antibodies directed against these pathways. We also discuss emerging therapeutic modalities, including next-generation antibody–drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies. Trastuzumab first established HER2-targeted therapy in gastric cancer, but the failure of trastuzumab emtansine (T-DM1) led to a decade-long stagnation until the advent of trastuzumab deruxtecan (T-DXd), which demonstrated robust clinical activity and defined a new standard of care. While bevacizumab failed to improve survival, the anti-VEGFR2 antibody ramucirumab emerged as an effective second-line therapy. Immune checkpoint inhibitors, including nivolumab and pembrolizumab, have been incorporated into first-line treatment for PD-L1-positive disease based on landmark trials such as CheckMate 649 and KEYNOTE-811. More recently, the CLDN18.2-targeted antibody zolbetuximab has expanded therapeutic options for biomarker-selected patients. Concurrently, a diverse pipeline of immune-based strategies—such as TROP2-directed ADCs, bispecific antibodies, and CAR-T cell therapies—is undergoing active clinical development. Together, advances in biomarker-driven antibody therapeutics are accelerating personalized cancer care and improving clinical outcomes in patients with gastric cancer. Full article

Background/Objectives: Several genetic alterations have been identified as drivers of uncontrolled cell growth in lung cancer, with KRAS mutations representing the most prevalent driver oncogene. Despite advances in targeted treatment, the 5-year survival rate of patients with advanced/metastatic NSCLC is still less than 20%. This study aims to assess the clinical relevance of KRAS mutations in the context of PD-L1 expression, focusing on patients with PD-L1 Tumor Proportion Score (TPS) ≥ 50% and treated with first-line immune checkpoint inhibitors (ICIs). Methods: We conducted a retrospective analysis of a real-world cohort comprising all staged NSCLC patients diagnosed and treated between 2018 and 2022 at our Institution with the available Next Generation Sequencing and PD-L1 immunohistochemistry results. Statistical analyses were made using the log-rank test, the two-tailed Fisher’s exact test, and Kaplan–Meier survival curves. Results: Among 520 NSCLC patients, 288 were adenocarcinoma (AC). Of these, 110/288 (38.2%) were KRAS mutants, and 83/278 (29.8%) presented a PD-L1 TPS ≥ 50%. In this subgroup, KRAS mutants demonstrated longer median overall survival (mOS) and progression-free survival (PFS) compared to the KRAS wild-type (28.7 vs. 10.7 months, p = 0.010; 6.4 vs. 3.5 months, p = 0.005, respectively). While OS did not differ among KRAS mutation subtypes, PFS was significantly shorter in patients with p.G12D (3.5 months, p = 0.03). Conclusion: This study is the first to investigate the interplay between KRAS mutations and PD-L1 expression in a real-world stage IV lung AC cohort treated with ICIs. Our findings indicate that the p.G12D mutation is associated with an extremely severe disease upon ICI monotherapy. These preliminary results need further validation in larger, prospective cohorts. Full article

The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8⁺ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial–mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME. Full article