Search Results (875)

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of tumors with a complex molecular profile. Despite therapeutic advances, patient prognosis remains poor, emphasizing the need for more effective treatment strategies. Traditional chemotherapy, with cisplatin and 5-fluorouracil (5-FU), remains the gold standard but is limited by toxicity and tumor resistance. Immunotherapy, particularly immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1), has improved overall survival, especially in patients with high PD-L1 expression. In parallel, targeted therapies such as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors—which impair DNA repair and increase replication stress—have shown promising activity in HNSCC. Cyclin-dependent kinase (CDK) inhibitors are also under investigation due to their potential to correct dysregulated cell cycle control, a hallmark of HNSCC. This review aims to summarize current and emerging pharmacotherapies for HNSCC, focusing on chemotherapy, immunotherapy, and PARP and CDK inhibitors. It also discusses the evolving role of targeted therapies in improving clinical outcomes. Future research directions include combination therapies, nanotechnology-based delivery systems to enhance treatment specificity, and the development of diagnostic tools such as PARP1-targeted imaging to better guide personalized treatment approaches. Full article

Background/Objectives: Bladder cancer is a malignant disease that causes more than 199,922 deaths a year globally, in which ~75% of all newly diagnosed cases are non-muscle-invasive bladder cancer (NMIBC). Despite a number of treatments available, most NMIBC patients with high-grade tumors eventually recur. To add a novel therapy to complement the deficits of the current treatments, this study assesses the antitumor activity and mechanisms of action of intravesical xenogeneic urothelial cell (XUC) treatment as monotherapy and in combination with either chemotherapy or immune checkpoint inhibition (ICI). Methods: The orthotopic NMIBC graft tumor-bearing mice were randomly assigned into different treatment groups, receiving either intravesical XUCs, gemcitabine, anti-programmed death-ligand 1 (PD-L1) antibodies alone or in combination with gemcitabine or anti-PD-1 antibodies. The tumor responses, survival, and immune reactions were analyzed. Results: Intravesical XUC treatment exhibited significantly more antitumor activity to delay tumor progression than the control group and a similar effect to chemotherapy and ICI. In addition, there were significantly higher effects in the combined groups than single treatments. Immune tumor microenvironment and immune cell proliferation, cytotoxicity, and cytokine secretion were also activated by XUC treatment. Moreover, the combined groups have the highest effects. Conclusions: In vivo and ex vivo studies showed increased antitumor efficacy and immune responses by intravesical XUC treatment in single and combined treatments, suggesting a potential utility of this xenogeneic cell immunotherapeutic agent. Intravesical XUC treatment has the potential to address the substantial unmet need in NMIBC therapy as a bladder-sparing treatment option for NMIBC. Full article

Glucocorticoids (GCs), such as dexamethasone (DEX), are commonly administered to glioblastoma (GBM) patients to control cerebral edema; however, their effects on immune checkpoint regulation in tumor cells remain insufficiently characterized. This study examined the impact of DEX on the expression of programmed death-ligand 1 (PD-L1) and glucocorticoid-induced leucine zipper (GILZ), a downstream effector of glucocorticoid receptor (GR) signaling, in the U87 and U251 glioblastoma cell lines. DEX consistently induced GILZ expression in both models yet elicited divergent effects on PD-L1: suppression in U87 cells and upregulation in U251 cells. In U87 cells, DEX-induced PD-L1 downregulation was accompanied by accelerated cell cycle progression, suggesting a dual impact on tumor immune evasion and proliferation. Mechanistically, GILZ silencing restored ERK phosphorylation and reversed PD-L1 suppression, whereas GILZ overexpression further decreased PD-L1 levels, implicating a GILZ–ERK pathway in the control of PD-L1. These findings uncover a previously unrecognized GR–GILZ–PD-L1 regulatory axis in glioblastoma cells. While these results are based on in vitro models, they provide a rationale for future in vivo studies to determine whether modulation of GILZ may influence immune checkpoint dynamics and therapeutic responsiveness in GBM. Full article

Tumor immunotherapy has revolutionized cancer treatment by harnessing the immune system to recognize and eliminate malignant cells, with immune checkpoint inhibitors targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) demonstrating remarkable clinical success. However, challenges such as treatment resistance, immune-related adverse effects, and high costs highlight the need for novel therapeutic approaches. Aptamers, short, single-stranded oligonucleotides with high specificity and affinity for target molecules, have emerged as promising alternatives to conventional antibody-based therapies. This review provides a comprehensive analysis of aptamer-based strategies targeting immune checkpoints, with a particular focus on PD-1/PD-L1 and CTLA-4. We summarize recent advances in aptamer design, including bispecific and multifunctional aptamers, and explore their potential in overcoming immune resistance and improving therapeutic efficacy. Additionally, we discuss strategies to enhance aptamer stability, bioavailability, and tumor penetration through chemical modifications and nanoparticle conjugation. Preclinical and early clinical studies have demonstrated that aptamers can effectively block immune checkpoint pathways, restore T-cell activity, and synergize with other immunotherapeutic agents to achieve superior anti-tumor responses. By systematically reviewing the current research landscape and identifying key challenges, this review aims to provide valuable insights into the future directions of aptamer-based cancer immunotherapy, paving the way for more effective and personalized treatment strategies. Full article

TP (tumor protein) 53 mutation status plays a critical role in cancer progression and may influence survival outcomes in non-small cell lung cancer (NSCLC) patients receiving immunotherapy. This study investigates the impact of TP53 mutation status and immunotherapy treatment on survival in NSCLC patients. This retrospective study analyzed NSCLC patients treated with pembrolizumab or ipilimumab plus nivolumab, stratified by TP53 mutation status and PD-L1 (programmed death-ligand 1) expression (<1%, 1–49%, >50%). Survival outcomes (overall survival (OS) and progression free survival (PFS) were assessed using Kaplan–Meier curves and log-rank tests, with subgroup analysis by histological subtype. In squamous cell cancer (SCC) patients, no significant differences in OS or PFS were found based on TP53 mutation status or treatment type. A trend toward improved survival was observed with pembrolizumab (p = 0.088). In adenocarcinoma patients, significant differences in OS and PFS were observed based on TP53 mutation status. Pembrolizumab showed superior survival outcomes compared to ipilimumab plus nivolumab in TP53 wild-type patients (p < 0.001). PD-L1 ≥ 1% also predicted better outcomes, especially in adenocarcinoma patients. TP53 mutation status and immunotherapy type significantly influence survival outcomes in NSCLC, particularly in adenocarcinoma patients. Pembrolizumab demonstrated superior efficacy in TP53 wild-type patients, with PD-L1 expression further refining survival predictions. These findings underscore the importance of personalized treatment strategies based on TP53 status and PD-L1 expression in NSCLC. Further studies are needed to validate these results and optimize treatment approaches. Full article

Breast cancer is the most frequently diagnosed cancer among women. In recent years, immunotherapy, a key targeted treatment strategy, has gained prominence in the management of this disease. Immune cells within the tumor microenvironment can significantly affect treatment outcomes. Among immunotherapeutic approaches, or programmed death protein 1(PD-1) and programmed death-ligand 1(PD-L1)-targeted therapies are increasingly recognized for their role in modulating cancer–immune system interactions. This study investigated the impact of PD-1/PD-L1 pathway inhibition on the expression of drug resistance-related proteins in an in vitro breast cancer model incorporating immune cells. MDA-MB-231 and MCF-7 cell lines were used as breast cancer cells, while THP-1 and Jurkat cells represented monocytes and lymphocytes, respectively. The effects of paclitaxel (PTX), doxorubicin (Dox), and PD-1/PD-L1 inhibitors (BMS-1166 and Human PD-L1 Inhibitor IV (PI4)) on cell viability were evaluated using an MTT assay, and the IC₅₀ values were determined. Flow cytometry was used to analyze PD-1/PD-L1 expression and the drug resistance proteins ABCG2 (ATP-binding cassette sub-family G member 2, breast cancer resistance protein), MDR-1 (multidrug resistance protein 1), and MRP-1 (multidrug resistance-associated protein 1) across co-culture models. Based on the results, Dox reduced PD-L1 expression in all groups except for MDA-MB-231:THP-1, while generally lowering drug resistance protein levels, except in MDA-MB-231:Jurkat. BMS-1166 significantly decreased cell viability and enhanced chemotherapy-induced cytotoxicity. Interestingly, in the MDA-MB-231:Jurkat co-culture, both inhibitors reduced PD-L1 but increased drug resistance protein expression. Paclitaxel’s effect on PD-L1 varied depending on the immune context. These findings highlight that PD-1/PD-L1 inhibitors and chemotherapeutic agents differentially affect PD-L1 and drug resistance-related protein expression depending on the immune cell composition within the tumor microenvironment. Full article

COVID-19 continues to spread six years after its discovery. Cancer patients are at an increased risk of severe outcomes, likely due to immunosuppression and tumor-related dysregulation. Programmed cell death protein 1 (PD-1), encoded by the PDCD1 gene, is a critical immune checkpoint involved in T-cell regulation. Since genetic polymorphisms can influence immune responses and individual susceptibility to SARS-CoV-2 infection, this case–control study aimed to investigate the association between the PDCD1 rs41386349 polymorphism and COVID-19 severity in individuals with and without cancer. This study included 279 COVID-19-positive and 160 negative individuals, genotyped by qPCR. COVID-19- positive cancer patients were significantly more likely to develop moderate (OR = 13.6) and severe (OR > 200) disease compared to cancer-negative individuals. No association was observed between the PDCD1 polymorphism and SARS-CoV-2 infection or disease severity, even after adjusting for cancer status, age and sex. However, age and sex were independently associated with severe outcomes: each additional year of age increased the odds of severe disease by 5.3%, and male patients had a three times higher risk of severe COVID-19. These findings confirm that cancer, male sex and older age are major predictors of worse prognosis in COVID-19, while the rs41386349 polymorphism alone does not appear to influence susceptibility or disease progression. Full article

The interaction of programmed cell death receptor 1 (PD-1) on the surface of immune cells with its ligand, programmed cell death ligand 1 (PD-L1), expressed on tumour cells and antigen-presenting cells, leads to tumour immune evasion. Antibodies that target either PD-1 or its ligand PD-L1 have shown a favourable response in cancer patients, especially those with non-small cell lung cancer (NSCLC). However, only 15 to 25% of advanced NSCLC patients will benefit from immunotherapy. The PD-L1 tumour proportion score (TPS) is the current standard biomarker to select patients for PD-1/PD-L1 blockade therapy, as patients with a high PD-L1 TPS show better response compared to patients with a low PD-L1 TPS. However, since PD-L1 expression is a continuous variable and is an imperfect biomarker, investigation into additional predictive markers is warranted. This review focuses on tumour- and non-tumour-associated factors that have been shown to affect the response to PD-1/PD-L1 inhibitors in NSCLC. We also delve into mechanistic and clinical evidence on these potential biomarkers and their relationship to the tumour microenvironment (TME). Full article

Introduction: Elderly patients with metastatic non-small-cell lung cancer (NSCLC) are underrepresented in clinical trials evaluating immune checkpoint inhibitors (ICIs). This study assesses the efficacy of first-line pembrolizumab monotherapy in patients with metastatic NSCLC aged ≥70 years with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥ 50%. Materials and Methods: We retrospectively analyzed 381 patients with metastatic NSCLC without oncogenic driver mutations treated with pembrolizumab monotherapy between 2017 and 2023 at three academic centers in Central and Southeastern Europe. Clinical outcomes, including median time on treatment (mToT) and overall survival (mOS), were compared between patients aged ≥70 and <70 years. Results: Of 381 patients, 149 (39.1%) were aged ≥70. No significant differences in mToT (12.7 vs. 14.3 months; p = 0.125) or mOS (18.2 vs. 27.4 months; p = 0.124) were observed between older and younger groups. Good ECOG PS (0–1) was independently associated with longer mToT and mOS in older patients. Additionally, a history of smoking was linked to improved outcomes compared to never-smokers, suggesting potential immunogenic effects. Older patients were significantly less likely to receive second-line therapy after progression (p = 0.04). Conclusions: First-line pembrolizumab monotherapy is effective across all age groups and provides similar treatment efficacy in patients with metastatic NSCLC and a PD-L1 TPS ≥ 50%. Patients older than 70 with a smoking history and ECOG PS 0–1 derive the most benefit from this treatment modality. The adaptation of this treatment strategy for elderly patients is especially important, since only a minority of them are capable of receiving second-line therapy. Full article

Human papillomavirus-mediated recurrent respiratory papillomatosis (RRP) is a premalignant neoplasia of the upper airway characterized by significant dysphonia and respiratory obstruction. Immune checkpoint blockade has emerged as a potential alternative to repeated surgical interventions in RRP. Here, we investigated the intralesional T-cell composition and expression of the immune checkpoints programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) in RRP. We analyzed tissue samples from 30 patients treated at a tertiary care center between 2009 and 2021, including paired samples from individual patients collected at different time points. Immunohistochemical staining was performed for CD4, CD8, CTLA-4, FoxP3, and PD-L1 and correlated with disease severity and previous adjuvant therapies. Overall disease burden and intervention-free survival were not associated with the abundance of CD4⁺, CD8⁺, or FoxP3⁺ T cells, nor with immune checkpoint expression. However, patients with aggressive disease exhibited a higher intralesional FoxP3/CD4 T-cell ratio. Prior intralesional cidofovir treatment was associated with reduced CD4⁺ T-cell infiltration. These findings suggest that a locally immunosuppressive microenvironment, reflected by an elevated FoxP3/CD4 ratio, contributes to disease severity in RRP. Consistent CTLA-4 expression across all evaluated samples supports further investigation of anti-CTLA-4 therapy, either alone or in combination with other checkpoint inhibitors. Full article

Background: Colorectal cancer is a significant health concern. Immunotherapy has become a promising approach in colorectal cancer, offering a wider array of therapeutic strategies. This study aims to summarize the current evidence regarding the use of checkpoint inhibitors in metastatic colorectal cancer. Methods: A systematic review of relevant clinical trials and randomized controlled trials (RCTs) assessing checkpoint inhibitors, published between January 2019 and January 2025, was conducted on Medline, Web of Science, and Cochrane. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were the primary outcomes. Studies focusing on other types of immunotherapy, non-clinical trials, pre-clinical trials, and study protocols were excluded. Results: 48 studies were included. Checkpoint inhibitors demonstrated significant efficacy in microsatellite instability (MSI) metastatic colorectal cancer (mCRC). In microsatellite stability (MSS) mCRC, immunotherapy was less effective, and combination strategies with chemotherapy or targeted therapies yielded mixed results. Grade ≥ 3 treatment-related adverse events (TRAEs) were common in combination regimens. Conclusion: Immunotherapy has revolutionized MSI mCRC treatment while treating MSS CRC with these molecules remains unconvincing. Combination strategies and novel agents may offer potential but require further research to prove efficacy. Full article

Programmed Death-Ligand 1 (PD-L1) is a major target for immunotherapy using checkpoint inhibitors (CPIs), particularly in lung cancer treatment. Tumoral PD-L1 expression has been recognized as a natural predictor of CPI response. This predictive relationship is primarily due to its upregulation by interferon-gamma, which is released by immune cells (mainly T lymphocytes and natural killer cells) in proximity to tumor cells, driving an immune resistance mechanism. However, PD-L1 expression is modulated at multiple levels, including oncogenic signaling pathways, and transcriptional and post-transcriptional regulations, potentially leading to false positive predictions. Conversely, variable glycosylation of PD-L1 may compromise the accuracy of immunohistochemical measurements, resulting in false negative predictive data. In addition, PD-L1 expression demonstrates relative instability throughout treatment courses (e.g., chemotherapy and tyrosine kinase inhibitors), further limiting its clinical utility. In this review, we focused on the molecular mechanisms governing PD-L1 expression with a special emphasis on lung cancer. We also discussed biomarker strategies for optimizing patient selection for checkpoint inhibitor therapy where multimodal/multi-omics meta-biomarker approaches are emerging. Such comprehensive PD-L1-enriched biomarker strategies require evaluation through large-scale prospective studies, particularly in lung cancer, where numerous competing predictive candidates exist for CPI response. Full article

The lymphocyte-specific transcription factor interferon regulatory factor 4 (IRF4) is a key player in immune evasion in cancers, with the complex mechanism(s) being barely understood. In this study, we have focused on the role of IRF4 in regulating T cell functions through its transcriptional regulation of programmed death 1 (PD1) and its ligand PD1 ligand 1 (PD-L1), which were identified as IRF4 transcriptional targets in multi-omics analysis. We have shown that IRF4 transcriptionally regulates both PD1 and PD-L1, promoting immune suppression in the context of Epstein–Barr virus (EBV) infection. Co-culturing EBV+ JiJoye lymphoma cells with CD4+ T cells or with peripheral blood mononuclear cells (PBMCs) downregulates CD4+ T cell functions, but the depletion of IRF4 in EBV+ JiJoye lymphoma cells reduces PD1 and PD-L1 expression, and partially restores CD4+ T cell functions. Moreover, CD4+ T cell depletion from PBMCs enhances EBV transformation, and EBV has a greater efficiency in transforming PBMCs from HIV patients with impaired CD4+ T cell functions. These findings support the role of IRF4 in immune evasion by upregulating PD1/PD-L1 during EBV transformation, and that functional CD4+ T cells are essential for limiting EBV transformation. Full article

Adjuvant treatment for resectable non-small cell lung cancer (NSCLC) has seen significant advancements following the introduction of immune checkpoint inhibitors (ICIs). These therapies, which enhance the immune system’s ability to recognize and target cancer cells, have demonstrated substantial improvements in disease-free survival (DFS) following surgical resection. Recent studies have shown that ICIs can extend DFS, particularly for patients with high Programmed Death-Ligand 1 (PD-L1) expression but also for those with lower levels of PD-L1, suggesting a broader potential for their application. In the IMpower010 trial, atezolizumab improved DFS compared to best supportive care (BSC) in resected stage II–IIIA NSCLC, with a hazard ratio (HR) of 0.66 (95% CI 0.50–0.88) for patients with PD-L1 expression ≥1% and 0.79 (95% CI 0.64–0.96) for the overall stage II–IIIA population. In the PEARLS/KEYNOTE-091 trial, pembrolizumab also demonstrated a DFS benefit over a placebo for patients with stage IB–IIIA disease (HR 0.76; 95% CI 0.63–0.91), with a median DFS of 53.6 months versus 42.0 months. Despite these promising results, challenges remain regarding the optimal selection of patients, particularly in identifying the most effective biomarkers and determining the ideal duration of treatment. While ICIs are generally well-tolerated, immune-related adverse events, although manageable, require careful monitoring, especially when ICIs are used in combination with chemotherapy. Ongoing research is focused on optimizing treatment duration and exploring combination therapies, with the objective of further improving long-term survival outcomes. The integration of immunotherapy in the adjuvant setting represents a significant advancement in the management of resectable NSCLC. This review aims to provide an overview of the current evidence supporting the use of ICIs in the adjuvant treatment of NSCLC, focusing on treatment efficacy, safety profiles, and ongoing research into biomarkers and combination therapies. Full article

It is becoming evident that the therapeutic effect of reawakening the immune response is to limit tumor cell growth and expansion. The use of immune checkpoint inhibitors, like blocking antibodies against programmed cell death receptor (PD) 1 and/or cytotoxic T lymphocyte antigen (CTLA) 4 alone or in combination with other drugs, has led to unexpected positive results in some tumors but not all. Several other molecules inhibiting lymphocyte antitumor effector subsets have been discovered in the last 30 years. Herein, we focus on the leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1/CD305). LAIR1 represents a typical immunoregulatory molecule expressed on almost all leukocytes, unlike other regulatory receptors expressed on discrete leukocyte subsets. It bears two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the intracytoplasmic protein domain involved in the downregulation of signals mediated by activating receptors. LAIR1 binds to several ligands, such as collagen I and III, complement component 1Q, surfactant protein D, adiponectin, and repetitive interspersed families of polypeptides expressed by erythrocytes infected with Plasmodium malariae. This would suggest LAIR1 involvement in several cell-to-cell interactions and possibly in metabolic regulation. The presence of both cellular and soluble forms of LAIR would indicate a fine regulation of the immunoregulatory activity, as happens for the soluble/exosome-associated forms of PD1 and CTLA4 molecules. As a consequence, LAIR1 appears to play a role in some autoimmune diseases and the immune response against tumor cells. The finding of LAIR1 expression on hematological malignancies, but also on some solid tumors, could open a rationale for the targeting of this molecule to treat neoplasia, either alone or in combination with other therapeutic options. Full article