Search Results (366)

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

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

The indications for immune checkpoint inhibitor (ICI) use in cancer treatment continue to expand. This is attributable to their proven anticancer activity in addition to their tolerability and favorable toxicity profile as compared to conventional chemotherapeutic agents. ICIs work by blocking the inhibitory signals between tumor cells and T-cells, thereby enhancing the T-cell cytotoxic activity to inhibit tumor growth. Because of their immune-stimulating effect, ICIs are linked to adverse renal outcomes in both native and transplanted kidneys. The risk of kidney allograft rejection in the setting of ICI use has been reported to be around 40%, leading to an increased risk of graft loss. In this report, we review the literature examining outcomes in kidney transplant recipients receiving ICIs for various oncologic indications. 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

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

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

Background and Objectives: Neuronal nitric oxide synthase (nNOS) overexpressed in melanoma plays a critical role in disease progression. Our previous studies demonstrated that nNOS inhibitors exhibited potent anti-melanoma activity and regulated PD-L1 expressions in the presence of interferon-gamma (IFN-γ). However, the role of nNOS in the melanoma immune response has not been well defined. Methods: Changes in gene expression profiles after nNOS inhibitor treatment were determined by transcriptomic analysis. A melanoma mouse model was used to determine the effects of nNOS inhibition on peripheral T cells and the in vivo anti-tumor activity of combining nNOS inhibitors with immune checkpoint blockade. Changes in human T cell activation through interleukin-2 (IL-2) production were investigated using an ex vivo co-culture system with human melanoma cells. Results: Cellular RNA analysis revealed significant changes in the genes involved in key signaling pathways after nNOS inhibitor HH044 treatment. Immunophenotyping of mouse peripheral blood mononuclear cells (PBMCs) after prolonged HH044 treatment showed marked increases in CD4⁺ and CD8⁺PD-1⁺ T cells. Ex vivo studies demonstrated that co-culturing human PBMCs with melanoma cells inhibited T cell activation, decreasing IL-2-secreting T cells both in the presence and absence of IFN-γ. PBMCs from a significant portion of donors (7/11, 64%), however, were reactivated by nNOS inhibitor pretreatment, displaying a significant increase in IL-2⁺ T cells. Distinctive T cell characteristics were noted at baseline among the responders with increased CD4⁺RORγt⁺ and reduced CD4 naïve T cells. In vivo mouse studies demonstrated that nNOS inhibitors, when combined with PD-1 blockade, significantly reduced tumor growth more effectively than monotherapy. Additionally, the median survival was extended from 43 days in the control mice to 176.5 days in mice co-treated with HH044 and anti-PD-1. Conclusions: Targeting nNOS is a promising approach to enhancing the anti-melanoma activity of immune checkpoint inhibitors, not only interfering with melanoma biological activities but also regulating the tumor microenvironment, which subsequently affects T cell activation and tumor immune response. Full article

Immune checkpoint inhibitors like programmed cell death 1 (PD-1) antibodies have revolutionized cancer treatment, but patient response rates remain limited. Sialic acid-binding Ig-like lectin 15 (Siglec-15) has emerged as a promising new immune checkpoint target. Through phage display technology using a Bactrian camel immunized with recombinant human Siglec-15, we generated six anti-Siglec-15 camelid nanobodies and constructed chimeric heavy-chain antibodies by fusing the VHH domains with human IgG-Fc. Following expression in HEK293-F cells and purification, three antibodies (S1, S5, S6) demonstrated specific binding to both human and murine Siglec-15 in ELISA and biolayer interferometry assays. In a xenograft model established by subcutaneous inoculation of NCI-H157-S15 cells into BALB/c nude mice, these antibodies showed distinct tumor targeting and significant blockade of Siglec-15 interactions with CD44, MAG, sialyl-Tn, and LRR4C ligands. All three antibodies exhibited anti-tumor effects, with S1 showing the most potent activity. S1-treated mice had significantly smaller tumor volumes and weights compared to controls. The S1, S5, and S6 treatment groups showed enhanced anti-tumor immunity, with reduced TGF-β, IL-6, and IL-10 levels. Notably, S1 treatment significantly increased tumor-associated macrophages in tumor tissues (p < 0.05). In conclusion, S1 exhibits remarkable anti-tumor activity and has the potential to be developed as a cancer immunotherapy targeting Siglec-15. Full article

Programmed death-ligand 1 (PD-L1) is a crucial immune checkpoint protein that tumors often exploit to evade immune surveillance. This study systematically screened a library of 1031 FDA-approved drugs using a high-throughput molecular dynamics approach to identify potential inhibitors targeting PD-L1. From this screening, five promising compounds—vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine—showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These candidates were further evaluated through extended molecular dynamics simulations lasting up to 150 ns to assess their structural stability, residue fluctuations, and binding free energy. Among the identified compounds, pivmecillinam demonstrated the most favorable results, exhibiting stable binding interactions and a binding free energy of −18.01 kcal/mol, comparable to that of the known PD-L1 inhibitor BMS-1. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents. Full article

Background/Objectives: Melanoma remains a difficult malignancy to treat because it employs tolerance mechanisms like negative immune checkpoint (IC) molecules to avoid antitumor immune responses. Thus, immune checkpoint inhibitors (ICIs) are increasingly used to treat melanoma. However, many patients do not respond, indicating resistance mechanisms like intrinsic tumor characteristics and an immunosuppressive tumor microenvironment (TME). An inflamed TME was associated with improved ICI efficacy by upregulating the T-cell inflamed TME gene signatures, an array of genes associated with dendritic cells (DCs) and cytotoxic CD8⁺ T-cell-mediated anti-tumor responses. As histone deacetylases (HDACs) have been shown to play crucial roles in regulating gene expression and aberrant HDAC expression has been reported in melanoma and also implicated in the regulation of IC, programmed cell death protein 1 (PD-1), and its ligand (PD-L1) and various immune evasion genes, we investigated the relationship between T-cell inflamed TME gene signatures and the HDAC family, particularly HDAC4. Methods: We used the skin cutaneous melanoma (SKCM) database, ICI-pretreated melanoma dataset, and other platforms including cBioPortal, TIMER 2.0, TISIDB, and UALCAN for the analysis. Results: We identified that high HDAC4 expression negatively modulated the TME by decreasing the abundance of DCs and cytotoxic CD8⁺ T-cells. The group of melanoma patients with elevated HDAC4 expression exhibited not only poor prognosis but also diminished transcription of T-cell inflamed TME gene signatures and increased DNA methylation of T-cell inflamed TME gene signatures. Importantly, elevated HDAC4 expression was associated with decreased CD8⁺ T-cells and a decreased ESTIMATE immune score in ICI-pretreated melanoma patients. Conclusions: Our findings suggest that HDAC4 may transform the TME into a non-inflamed phenotype, thereby reducing ICI efficacy in melanoma. Overall, this research shows that a combination of HDAC4 inhibitors and ICIs could result in better melanoma prognosis. Full article