Search Results (1,026)

Background/Objectives: Recent advances in immunotherapy have revolutionized cancer treatment, as exemplified by multiple monoclonal antibodies against programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1). Nevertheless, immunotherapeutic antibodies exhibit certain limitations, which drives the development of alternative approaches, such as small interfering RNA (siRNA)-based therapeutics. The aim of this study was to design and produce new biological PD-L1 siRNA (BioRNA/PD-L1-siRNA) molecules and further define their immunotherapeutic efficacy against non-small cell lung cancer (NSCLC) in vitro. Methods: A novel RNA molecular bioengineering platform was employed to produce new BioRNA/PD-L1-siRNA agents. The functions of BioRNA/PD-L1-siRNAs were determined by quantitative PCR, Western blot, immunofluorescence confocal imaging, flow cytometry, and PD-1/PD-L1 blockade assays in human NSCLC cells, alone and co-cultured with human peripheral blood mononuclear cells (PBMCs). Results: After heterologous overexpression and purification of five BioRNA molecules, one siRNA named BioRNA/PD-L1-siRNA-1 was identified as the most effective to selectively suppress human PD-L1 mRNA and protein levels in H460 and H1975 cells. Disruption of PD-1/PD-L1 interactions by BioRNA/PD-L1-siRNA-1 was further demonstrated via a PD-1/PD-L1 blockade bioassay. In addition, the immunomodulatory effectiveness of BioRNA/PD-L1-siRNA-1 was established in co-culture models, as indicated by the induction of T-cell and natural killer cell populations and an increase in specific cytokines and cytotoxic granules, and subsequent enhancement of apoptosis and greater inhibition of NSCLC cell viability. Conclusions: Overall, these findings demonstrate the potential of bioengineered PD-L1 siRNA entities for NSCLC immunotherapy. Full article

Thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas, are rare, biologically heterogeneous thoracic malignancies with limited therapeutic advances since platinum-based regimens were adopted decades ago. Recent genomic and immunophenotypic profiling has uncovered recurrent genomic alterations and high programmed death-ligand 1 (PD-L1) expression, particularly in thymic carcinoma, yet few targeted or immunotherapies have achieved regulatory approval. This mini-review synthesizes current knowledge on TET heterogeneity and the genomic landscape, evaluates the clinical evidence supporting targeted agents and immune checkpoint inhibitors, and examines emerging biomarkers, including circulating tumor DNA. We also address practical barriers to precision oncology in TETs: challenges of next-generation sequencing implementation and cost in resource-limited settings; scarcity of large, biomarker-driven trials; and safety concerns unique to TETs (immune-related toxicity). Finally, we discuss the translational hurdles for antibody–drug conjugates and cellular therapies, limited validated cell surface targets, antigen heterogeneity, and preclinical model gaps and outline strategic paths forward to enable rational, safe, and equitable precision therapeutics for TET patients. Full article

Background/Objectives. Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint protein that enables tumors to evade immune surveillance by suppressing T cell activation. Monoclonal antibodies are currently used to modulate PD-1/PD-L1 interactions. However, several immune-associated adverse effects were ascribed to those treatments. This led to the necessity for small-molecule alternatives like BMS-202. Methods. In this study, we investigated the temporal dynamics of cell-surface PD-L1 in response to the small-molecule dimerizer BMS-202. Treatment with a non-cytotoxic concentration of BMS-202 at 5 µM triggered a transient reduction in surface PD-L1 concentration, reaching its lowest level at 15 min. In the attempt to characterize the fate of PD-L1 following exposure to the BMS-202 dimerizer, we employed a low-pH wash internalization assay. Results. The results demonstrated a transient increase in intracellular PD-L1 within 5–15 min of compound exposure, followed by rapid recovery of surface PD-L1 levels. These findings suggest that BMS-202-induced changes in surface PD-L1 are acute and reversible, with levels returning to baseline within 24 h post-exposure. Conclusions. These findings reveal a dynamic regulatory mechanism where small-molecule-induced dimerization triggers rapid protein trafficking and transient surface depletion. Understanding these temporal dynamics is essential for the development of next-generation small-molecule immune checkpoint inhibitors. Full article

Pancreatic cancer ranks among the most lethal malignancies, characterized by a five-year survival rate of approximately 10%. This dismal prognosis is largely attributable to diagnoses occurring at advanced stages and the inherent limitations of conventional imaging modalities in detecting early lesions, identifying metastases, and assessing tumor heterogeneity. Consequently, there is a critical need for non-invasive imaging techniques capable of visualizing pancreatic cancer lesions to enable accurate diagnosis, risk assessment, and the development of personalized treatment strategies. Molecular imaging, which combines highly specific targeted probes with advanced imaging technologies, offers the potential to elucidate disease-associated pathways. This review provides a comprehensive overview of recent advancements in molecular imaging platforms for pancreatic cancer, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), optical molecular imaging, photoacoustic imaging, and molecular MRI. We begin by elucidating the biological rationale for targeting key molecules, including fibroblast activation protein (FAP), integrins, and programmed death ligand 1 (PD-L1). Moreover, we critically evaluate the development and clinical translation of these probes, highlighting their ability to enhance lesion detectability, characterize intratumoral heterogeneity, and guide both targeted therapy and surgical resection. Compared with existing reviews, this work uniquely integrates a comprehensive cross-modality analysis of the latest molecular imaging strategies for pancreatic cancer. Furthermore, we examine prevailing challenges and emerging frontiers in this domain, specifically focusing on multimodal hybrid imaging, artificial intelligence-driven analytics, and integrated theranostic platforms as pivotal strategies to advance precision oncology. Full article

The zinc finger protein 36 (ZFP36) family, including ZFP36/tristetraprolin (TTP), ZFP36 CCCH-type-like 1 (ZFP36L1), and ZFP36 CCCH-type-like 2 (ZFP36L2), consists of conserved CCCH-type tandem zinc-finger RNA-binding proteins. These proteins recognize AU-rich elements (AREs) in target mRNAs and promote deadenylation, decay, and translational repression. In this review, we use the term post-transcriptional immune checkpoint in a restricted conceptual sense: ZFP36 family proteins are intracellular, RNA-level negative regulators that tune the magnitude, duration, and resolution of immune effector programs, rather than classical receptor-ligand immune checkpoints such as programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). We summarize structural features, ARE-recognition mechanisms, mRNA decay pathways, translational repression mechanisms, and post-translational regulation of the ZFP36 family, while explicitly distinguishing mechanisms established for ZFP36 from those inferred for ZFP36L1 and ZFP36L2. We then review cell-type-specific roles in innate and adaptive immunity, including myeloid inflammatory responses, barrier tissue inflammation, innate lymphoid cell function, T cell activation and effector differentiation, regulatory T cell stability, B cell development, and antiviral immunity. In cancer, ZFP36 family members show context-dependent functions that should be separated into tumor-cell-intrinsic effects and immune-microenvironment-dependent effects. They suppress tumor progression by destabilizing pro-inflammatory, angiogenic, metabolic, and epithelial–mesenchymal transition (EMT)-associated transcripts, yet may also restrict antitumor immune responses or promote immune evasion in selected tumor contexts. Finally, we discuss autoimmune and inflammatory diseases, allergic disorders, transplant immunity, neuroimmune relevance, and therapeutic strategies, emphasizing the current evidentiary limits, preclinical status, and safety concerns of ZFP36 family modulation. Full article

Background/Objectives: Published data on reliable prognostic biomarkers for pulmonary pleomorphic carcinoma (PPC), a rare, aggressive subtype of non-small cell lung cancer, are limited. Programmed death-ligand 1 (PD-L1) has been studied; however, the prognostic impact of other immunoregulatory molecules, such as CD73, CD155, and Ki-67 and their combined expression profiles, remains unclear. Methods: We retrospectively analyzed data of 47 patients who had undergone macroscopic complete resection of PPC between January 2000 and December 2022. Immunohistochemistry for PD-L1, CD73, CD155, and Ki-67 was performed. Cut-off values were determined by receiver operating characteristic analysis for cancer-specific death. The primary endpoint was the association between each biomarker and overall survival (OS) or cancer-specific survival (CSS). The secondary endpoint was the prognostic value of combined biomarker profiles, particularly PD-L1 with CD73, CD155, or Ki-67. Results: At a positivity threshold of 1%, the positivity rates were 70.2% for PD-L1, 89.4% for CD73, 91.5% for CD155, and 83.0% for Ki-67. There were no statistically significant differences in OS or CSS between groups with high expression and those with low expression for any single marker. Secondary endpoint analysis showed that low PD-L1 and low CD73 predicted significantly poorer OS (p = 0.046) and low PD-L1 and low Ki-67 predicted significantly poorer CSS (p = 0.039) compared with other combinations. Conclusions: Primary endpoint analyses showed no statistically significant association between any single marker and prognosis in PPC. In contrast, secondary endpoint findings indicated that concurrent low PD-L1 with either low CD73 or low Ki-67 identified subsets with significantly poorer outcomes. The present findings provide a basis for further investigation of biomarker combinations for prognostic assessment in this rare lung cancer. Because of the limited sample size, these findings are exploratory and require validation in larger independent cohorts. Full article

Background and Objectives: Clear cell renal cell carcinoma (ccRCC) demonstrates substantial molecular and clinical heterogeneity, limiting the prognostic accuracy of conventional staging system and complicating treatment selection. CT-based radiomics and radiogenomics have emerged as promising non-invasive approaches for predicting molecular biomarkers. This review aimed to evaluate the current evidence regarding CT-based radiogenomics for the prediction of molecular markers in ccRCC, with emphasis on methodological approaches, predictive performance, and clinical applicability. Materials and Methods: A comprehensive literature search of PubMed/MEDLINE, Scopus, and Cochrane Library databases was performed for original studies published between January 2012 and December 2025. Eligible studies included patients with histopathologically confirmed ccRCC, performed CT-based radiomics feature extraction, and investigated molecular or genetic biomarkers using machine learning (ML) methods. Data regarding CT acquisition phase, segmentation strategy, radiomics features, ML algorithms, investigated biomarkers, and model performance metrics were extracted. Results and Discussion: Twenty-five retrospective studies were included. CT-based radiomics demonstrated promising performance in predicting gene mutations, including Von Hippel–Lindau (VHL), Polybromo 1 (PBRM1), BRCA1-associated protein 1 (BAP1), SET domain containing 2 (SETD2), and Lysine demethylase 5C (KDM5C), with reported area under the curve (AUC) values reaching 0.987. Radiogenomic models also showed utility in assessing hypoxia-related pathways, lipid metabolism signatures, programmed cell death profiles, immune-related markers, and tumor microenvironment characteristics, including programmed death-ligand 1 (PD-L1), Cluster of Differentiation 68 (CD68+) tumor-associated macrophages (TAMs), Cytotoxic T-Lymphocyte–Associated Protein 4 (CTLA-4), Forkhead Box P3 (FOXP3), and Ki-67 proliferation index. Predictive performance varied across biomarkers, with AUCs generally ranging from 0.68 to 0.91. Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), Adaptive Boosting (AdaBoost), and Gradient Boosting algorithms were most commonly applied. Conclusions: CT-based radiogenomics represents a promising non-invasive tool for molecular characterization and risk stratification in ccRCC. Standardized multicenter prospective studies, methodological homogeneity, and external validation are required before routine clinical implementation. Full article

Background and Clinical Significance: Brain metastases in non-small cell lung cancer (NSCLC) carry a poor prognosis, particularly in patients lacking targetable driver mutations or significant programmed death-ligand 1 (PD-L1) expression. Durable intracranial control exceeding five years is uncommon in this population and the factors that determine exceptional therapeutic response remain incompletely understood; Case Presentation: We report a 59-year-old male with pathological stage pT3N1 solid-type pulmonary adenocarcinoma (EGFR wild-type, ALK wild-type, PD-L1 <1%) who developed two sequential brain metastases following right upper lobectomy and adjuvant pembrolizumab plus pemetrexed-carboplatin. The first lesion was treated with single-fraction stereotactic radiosurgery (SRS, 10 Gy); a second metastasis identified 18 months later was managed with focal radiotherapy (8 Gy, single fraction) followed by whole-brain radiotherapy (24 Gy in 12 fractions). Local progression of the second metastasis in 2024 prompted successful surgical resection via right occipital craniotomy. Over a follow-up exceeding five years, the patient achieved sustained intracranial disease control, preserved neurological function, and maintained quality of life. Notably, no clinically apparent neurocognitive deterioration was documented on routine clinical follow-up, despite whole-brain irradiation without hippocampal sparing; formal neuropsychological testing was not performed; Conclusions: This case demonstrates that durable intracranial control may be achievable through carefully sequenced multimodal therapy—including stereotactic radiosurgery, whole-brain radiotherapy, and neurosurgical resection—even in biologically unfavorable NSCLC. The absence of clinically apparent neurocognitive deterioration on routine follow-up after WBRT raises hypothesis-generating questions regarding interindividual variability in radiation tolerance; this observation must be interpreted in the absence of formal neuropsychological testing and prospective hippocampal dosimetry. A multidisciplinary, individualized approach integrating radiotherapy, systemic therapy, and neurosurgery remains essential in this setting. Full article

Gastric cancer remains a major cause of cancer-related mortality worldwide, highlighting the need for an improved understanding of its molecular mechanisms. Purinergic and glutamatergic signaling pathways, immune checkpoint molecules, and oxidative stress are thought to contribute to tumor biology; however, their combined evaluation in gastric cancer is limited. Methods: Gene expression levels of glutamate receptor ionotropic N-Methyl-D-aspartate 2A (GRIN2A), purinergic receptor P2X1 (P2RX1), and programmed death-ligand 1 (PD-L1/CD274) were analyzed using real-time PCR, while serum protein levels were determined by ELISA. Total antioxidant status (TAS) and total oxidant status (TOS) were also measured to assess systemic oxidative balance. Results: Gene expression analysis revealed an increased expression trend for P2RX1 in the gastric cancer group compared with healthy controls, whereas GRIN2A and CD274 (PD-L1) expression levels showed numerical decreases. Serum concentrations of GRIN2A and PD-L1, as well as TAS and TOS levels, were numerically higher in patients with gastric cancer; however, none of these differences reached statistical significance (p > 0.05). Likewise, serum P2RX1 levels did not differ significantly between groups. Receiver operating characteristic (ROC) analysis demonstrated area under the curve (AUC) values close to 0.5 for all evaluated parameters, indicating limited discriminatory and diagnostic performance. Conclusions: These findings suggest that these molecular markers may reflect disease-related biological alterations rather than serve as independent circulating diagnostic biomarkers in gastric cancer. Full article

Background: Overexpression of programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) induces immune evasion by cancer cells. Nivolumab and pembrolizumab (anti-PD-1 antibodies) are used to treat advanced non-small cell lung cancer (NSCLC). However, objective response rates are limited (20–30%), indicating that individual tumor microenvironments may differ according to immune evasion processes. Therefore, the development of biomarkers predictive of responders to immune checkpoint inhibitors is necessary. Activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) signaling pathway promotes lung cancer cell growth and resistance to chemotherapy, radiotherapy, targeted therapy, and PD-1/PD-L1 inhibition. The present study investigated whether NRF2 expression in NSCLC is associated with clinicopathological factors, the expression levels of intratumoral PD-L1 and CD8, and the efficacy of anti-PD-1 monotherapy. Methods: NRF2, PD-L1, and CD8 expression on tumor cells and tumor-infiltrating lymphocytes were examined by immunohistochemistry in 54 patients with advanced adenocarcinoma (N = 40) and squamous cell carcinoma (N = 14) treated with nivolumab or pembrolizumab. Histological subtypes, tumor stages, and other clinicopathological features were compared with their expression levels. Results: Weak NRF2 staining was significantly correlated with high levels of PD-L1 and CD8+ tumor-infiltrating lymphocytes, and a favorable response to treatment with nivolumab or pembrolizumab in NSCLC. Progression-free survival of patients treated with anti-PD-1 therapy differed according to the different NRF2 levels. Conclusions: NRF2 overexpression in NSCLC is associated with resistance to PD-1 blockade monotherapy. Full article

Background: Pembrolizumab-containing regimens have become the standard of care across the spectrum of triple-negative breast cancer (TNBC). While their use in the neoadjuvant setting is independent of biomarker status, their application in metastatic disease remains strictly contingent upon PD-L1 expression. Given that PD-L1 prevalence can vary significantly by ethnicity and geography, the lack of specific data for the Mexican population creates a challenge for optimizing treatment in the metastatic setting. This study sought to characterize PD-L1 positivity rates in a Mexican TNBC cohort to better define the local molecular landscape. Methods: We conducted a retrospective study across two cancer centers in Mexico to assess PD-L1 positivity in a cohort of women with TNBC (stages I–IV) diagnosed between 2006 and 2021. PD-L1 expression was assessed and evaluated centrally using the 22C3 pharmDx assay, with a Combined Positive Score (CPS) of ≥1 considered positive. We explored the association between PD-L1 expression and clinicopathological features. Results: Of the 298 TNBC patients identified, 285 (96%) had sufficient tissue for CPS evaluation and thus were included in the analysis. PD-L1 positivity was observed in 29.1% of the cohort, and 13.3% of patients had a CPS ≥ 10. PD-L1 positivity was associated with higher histological grades (91.3% vs. 78.5%, p = 0.035) and TILs ≥ 30% (22.2% vs. 10.0%, p = 0.007). Additionally, pre-treatment surgical specimens were more frequently PD-L1 positive than tumor biopsies (56.6% vs. 30.7%, p < 0.001). Conclusions: This study characterizes the PD-L1 landscape in Mexican women with TNBC, reporting a 29.1% prevalence of CPS ≥ 1. The strong association between PD-L1 positivity and high TILs/histological grade highlights the role of the immune microenvironment in these aggressive phenotypes. Given the significant variability observed between specimens (biopsy vs. surgical), clinicians should consider the dynamic nature of PD-L1 expression when choosing treatment strategies. Full article

Hepatocellular carcinoma (HCC) is a heterogeneous primary liver malignancy characterized by limited treatment options and low overall survival rates. Recent studies have explored the role of programmed death ligand 1 (PD-L1), tumor-associated macrophages (TAMs), and epithelial-mesenchymal transition (EMT) in modulating tumor progression and the response to immunotherapy. This study aimed to investigate the association among PD-L1 expression, TAMs, and EMT in HCC, highlighting the recently proposed immunophenotypic variant—gastric-type HCCs. A retrospective cohort of 50 surgically resected HCC patients was analyzed. Immunohistochemical staining was performed for PD-L1 (clones 28-8 and 22C3), CD68 (TAMs), and EMT markers (VSIG-1, TTF-1, and vimentin). PD-L1 expression was detected in 52% of the patients and was significantly associated with high TAM counts (p < 0.001). Compared with PD-L1-negative patients, those with gastric-type HCCs, which are characterized by VSIG-1 and TTF-1 co-expression and vimentin negativity, demonstrated improved survival outcomes (p = 0.03). Integration of immune and EMT profiling of tumor cells in routine diagnostics may guide prognosis and immunotherapeutic strategies in HCC. Further molecular validation is required to confirm the biological significance of the proposed gastric-type HCC immunophenotype. Full article

Background: Immune checkpoint inhibitors (ICIs), particularly programmed death-ligand 1 (PD-L1) inhibitors such as atezolizumab, have significantly improved outcomes in cancer therapy. However, these agents may cause immune-related adverse effects, including nephrotoxicity associated with oxidative stress and cellular stress responses. This study aimed to investigate and comparatively evaluate the protective effects of adenosine triphosphate (ATP) and taxifolin against atezolizumab-induced renal tissue injury in rats. Methods: Animals were divided into four groups: healthy (HG), atezolizumab (ATZ), ATP + atezolizumab (ATAZ), and taxifolin + atezolizumab (TXAZ). ATP (4 mg/kg, i.p.) and taxifolin (50 mg/kg, oral) were administered for six days, while atezolizumab (10 mg/kg, i.p.) was given on days 1 and 4. On day 7, renal tissues were collected for biochemical, histopathological, and double immunofluorescence analyses. Results: Atezolizumab significantly increased malondialdehyde (MDA) levels and decreased total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) levels, indicating enhanced oxidative stress and impaired antioxidant defense. These changes were accompanied by tubular degeneration and increased expression of apoptotic markers. Both ATP and taxifolin significantly ameliorated these alterations; however, ATP demonstrated a more pronounced protective effect. Conclusions: In conclusion, ATP and taxifolin attenuated the biochemical, histopathological, and immunofluorescence alterations associated with atezolizumab administration. ATP exhibited a more pronounced protective effect than taxifolin under the conditions of this experimental model. Nevertheless, further experimental studies are required to elucidate the mechanisms underlying these effects. Full article

In triple-negative breast cancer (TNBC), immune checkpoint pathways play a central role in tumor immune evasion. Programmed death protein 1 (PD-1) is an inhibitory receptor expressed on T cells, while its ligand, programmed death-ligand 1 (PD-L1), is commonly expressed on tumor cells and cells within the tumor microenvironment. Their interaction suppresses T-cell activation and promotes immune escape. In this study, we evaluated the potential of small interfering RNA (siRNA) to silence PD-L1 expression in TNBC. Transcriptomic analysis of GEO datasets revealed consistent upregulation of CD274 (PD-L1) in TNBC samples. Three siRNA candidates were designed and evaluated in MDA-MB-231 cells. All siRNAs significantly reduced CD274 expression (>70%), as determined by RT-qPCR. Immunofluorescence analysis confirmed a reduction in PD-L1 protein levels (54.3 vs. 98.7 a.u.), while MTT assays demonstrated preserved cell viability at the working concentration (100 pM), supporting a non-cytotoxic and specific gene-silencing effect. These findings highlight PD-L1 as a viable molecular target and support siRNA-mediated silencing as a promising therapeutic strategy in TNBC. Full article

Immune checkpoint inhibitors (ICIs), comprising anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1), and anti-programmed death-ligand 1 (PD-L1), have transformed melanoma therapy, yet the tumour microenvironment (TME), the pivotal biological interface where therapeutic efficacy, resistance, and toxicity are determined, remains incompletely characterized. This dual systematic review and meta-analysis (PROSPERO: CRD420261374242) followed PRISMA 2020 and included 58 preclinical (B16F10/C57BL/6; 46 quantitative) and 44 clinical studies (19 quantitative) to calculate pooled standardized mean differences (SMDs) for six intratumoral TME parameters. Checkpoint blockade consistently shifted the TME toward an immune-activated state, an effect that remained robust in sensitivity analyses despite substantial heterogeneity (I-squared heterogeneity statistic (I²) = 68–88%). Preclinically, ICIs significantly increased CD8⁺ T-cell infiltration (SMD = 1.45, p < 0.001), interferon-gamma (IFN-γ) (SMD = 1.78, p < 0.001), CD8/regulatory T-cell (Treg) ratio (SMD = 0.91, p = 0.005), and apoptosis (SMD = 3.54, p < 0.001) and reduced PD-L1 (SMD = −0.88, p = 0.004) and Ki-67 (SMD = −1.43, p = 0.028). Clinically, CD8⁺ infiltration and PD-L1 both increased (SMD = 0.72, p < 0.001; SMD = 0.67, p = 0.001), contrasting with the preclinical PD-L1 decrease. Meta-regression demonstrated superior anti-PD-L1 efficacy over CTLA-4 for effector parameters: IFN-γ +3.59 (p = 0.009), CD8/Treg +10.69 (p = 0.003), apoptosis +9.76 (p = 0.004), and Ki-67 −6.28 (p = 0.040). These findings establish the TME as a critical determinant of ICI outcomes, indicate that PD-L1 amplifies effector functions in the B16F10 model, and highlight translational gaps in TME reprogramming. Full article