Search Results (6,284)

Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8⁺ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target. Full article

Importance: Triple-negative breast cancer (TNBC) is characterized by high tumor mutation burden and frequent programmed cell death ligand 1 (PD-L1) expression, making immune checkpoint inhibitors (ICIs) a promising therapeutic approach. However, randomized trials of chemoimmunotherapy (Chemo-IO) in locally recurrent unresectable or metastatic TNBC have shown inconsistent results, necessitating a clearer understanding of efficacy and patient selection. Objective: The aim of this study was to evaluate the efficacy and safety of chemotherapy combined with immunotherapy vs. chemotherapy alone in patients with locally recurrent unresectable or metastatic triple-negative breast cancer and to identify beneficiary populations to guide optimal treatment selection. Data Sources: PubMed, Embase, and the Cochrane Library were searched from database inception through 23 August 2025. Study Selection: Randomized clinical trials (RCTs) comparing chemotherapy combined with ICIs vs. chemotherapy with placebo or control in patients with locally recurrent unresectable or metastatic TNBC were selected. Data Extraction and Synthesis: Two investigators independently performed data extraction and assessed risk of bias using the Cochrane Risk of Bias 2 tool (RoB 2). Heterogeneity was evaluated using the I² statistic. Data were synthesized using random-effects meta-analysis models to calculate hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for dichotomous outcomes according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Results: Seven RCTs comprising 3485 patients (2085 in the Chemo-IO group, 1400 in the control group) were included. The median age across trials ranged from 52 to 57 years. Chemo-IO significantly improved PFS (HR, 0.82 [95% CI, 0.76–0.89]; p < 0.01) and OS (HR = 0.88; 95% CI: 0.81–0.96; p = 0.004) in the intention-to-treat (ITT) population, with PFS benefit particularly evident in PD-L1-positive patients (HR = 0.68, 95% CI: 0.59–0.79). However, OS improvement in the PD-L1-positive subgroup was not statistically significant. CBR did not differ significantly in the intention-to-treat population (RR, 1.11 [95% CI, 0.99–1.25]; p =  0.08) but was higher in PD-L1-positive patients (RR, 1.15 [95% CI, 1.01–1.31]; p = 0.04). Safety analyses revealed no significant differences in overall AE (RR, 1.01 [95% CI, 0.99–1.02]; p = 0.35), TEAE (RR, 1.01 [95% CI, 0.99–1.03]; p = 0.19), or grade ≥ 3 TEAE (RR, 1.00; [95% CI, 0.93–1.07]; p =  0.98). However, serious AE (RR, 1.32 [95% CI, 1.11–1.57]; p = 0.001) and irAE (RR, 1.86 [95% CI, 1.41–2.45]; p <  0.01) were more frequent with Chemo-IO. Conclusions and Relevance: Chemotherapy combined with immunotherapy significantly improved PFS and OS in patients with locally recurrent unresectable or metastatic TNBC, without substantially increasing chemotherapy-related toxicities. However, the OS benefit in PD-L1-positive patients was not statistically significant, and the combined regimen was associated with higher rates of serious and immune-related adverse events. These findings support the use of Chemo-IO as a treatment option, highlighting the importance of PD-L1 status and careful monitoring of immune-mediated toxicities in clinical practice. Full article

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and although PD-1/PD-L1 immune checkpoint blockade has improved outcomes in some patients, therapeutic responses remain heterogeneous. Tumor-intrinsic heterogeneity within malignant epithelial populations is increasingly recognized as a critical determinant of disease progression and therapy response. Methods: Here, we constructed a comprehensive single-cell atlas of NSCLC by integrating 650,461 cells from 216 tumor and normal samples. Tumor-derived epithelial cells were reclustered to identify transcriptionally distinct subpopulations. Pseudotime analysis, functional experiments, and in vivo validation using a humanized xenograft model were performed to investigate the role of COL3A1. Results: Reclustering of tumor-derived epithelial cells revealed 25 transcriptionally distinct subpopulations. Among these, a high-risk cluster exhibited coordinated activation of epithelial–mesenchymal transition (EMT) and angiogenesis programs and was associated with poor patient survival. Within this aggressive subpopulation, Collagen type III alpha 1 (COL3A1) emerged as a tumor-intrinsic gene associated with extracellular matrix remodeling and angiogenic signaling. Pseudotime analysis indicated that COL3A1⁺ cells represent a late-stage, poorly differentiated malignant state. Functional experiments demonstrated that COL3A1 knockdown impaired NSCLC cell proliferation, migration, and invasion. Virtual knockout further suggested that COL3A1 may be associated with transcriptional programs involved in PD-L1 upstream signaling pathways, indicating a potential indirect link between tumor-intrinsic states and immune regulatory networks. Consistently, in vivo silencing of COL3A1 enhanced the antitumor efficacy of PD-L1 blockade. Conclusions: Collectively, our study identifies COL3A1 as a tumor-intrinsic gene enriched in malignant epithelial cells with mesenchymal features and a potential therapeutic target. These findings provide a rationale for exploring combinatorial strategies integrating tumor-intrinsic pathway inhibition with immune checkpoint blockade in NSCLC. Full article

Background/Objectives: Oocyte donation (OD) pregnancies involve complete maternal–fetal genetic disparity and are associated with increased placental dysfunction and adverse perinatal outcomes. However, a unified histopathological framework to characterize alloimmune-mediated placental injury in OD gestations is lacking. This study evaluates immune and vascular alterations in OD triplet placentas and proposes a structured scoring system, the Placental Allograft Rejection-like Score (PARS), to quantify immunovascular dysregulation. Methods: This retrospective study included all OD triplet pregnancies with placental examination performed during 24 years at a tertiary referral center. Maternal, obstetric, fetal, neonatal, and pathological variables were analyzed at the pregnancy level. Histological and immunohistochemical features previously shown to differ between OD and non-OD pregnancies were grouped into six domains: innate immunity, adaptive immunity, checkpoint regulation, vascular remodeling, complement activation, and trophoblastic behavior. Binary thresholds, immunoreactive scores or established morphological cut-offs, were applied to construct a 20-point score classified into three grades. Results: Forty-five OD triplet pregnancies were analyzed. Intra-pregnancy concordance for PARS components was high, with intraclass correlation coefficient ≥0.70 in 87.3% pregnancies. Increasing PARS grades demonstrated a clear clinical gradient. Grade 3 pregnancies had significantly lower birthweight, higher rates of prematurity (<34 weeks), and increased fetal growth restriction. Placental weight decreased progressively with higher PARS. Histologically, grade 3 placentas showed significantly increased accelerated villous maturation and intervillous fibrin deposition. Conclusions: PARS integrates immune and vascular placental lesions into a structured and reproducible framework that correlates with clinically relevant perinatal outcomes and may support future clinical risk stratification, although further validation in larger, multicenter prospective cohorts is required. Full article

Cancer immunotherapy has transformed oncology, including the management of urothelial carcinoma, yet response rates remain limited and mechanisms of resistance are incompletely understood. At the same time, recent initiatives from the National Institutes of Health and the United States Food and Drug Administration have emphasized the development of standardized human organoid platforms to improve preclinical modeling and reduce reliance on traditional animal systems. Urothelial cancer provides a compelling context in which to advance these efforts, given its established responsiveness to Bacillus Calmette–Guérin and immune checkpoint blockade and its marked heterogeneity in clinical outcomes. Here, we review current organoid-based platforms for modeling bladder cancer immunotherapy, including patient biopsy-derived epithelial tumor organoids, air–liquid interface cultures that retain endogenous stromal and immune components, engineered bladder cancer assembloids that reconstruct defined multicellular circuits, and induced pluripotent stem cell-derived urothelial organoids that offer renewable multilineage systems. For each approach, we outline strengths, technical constraints, and limitations in scalability, immune fidelity, and genetic matching. We conclude by discussing the critical challenges that must be addressed—including benchmarking to patient tumors, reproducibility across laboratories, and standardized validation metrics—to enable regulatory acceptance and clinical translation of organoid-based immunotherapy testing. Full article

The bone marrow tumor microenvironment (TME) is critical for acute myeloid leukemia (AML) progression, immune evasion, and treatment resistance. SRC, a non-receptor tyrosine kinase involved in multiple oncogenic pathways, has not been systematically characterized in AML in relation to prognosis and immune regulation. We integrated bulk transcriptomic and single-cell RNA-sequencing datasets from TCGA, BeatAML, and GEO. Immune-related targets were identified using xCell-based immune scoring and weighted gene co-expression network analysis (WGCNA), followed by protein–protein interaction analysis and multi-algorithm machine-learning screening. We then evaluated SRC expression patterns, prognostic associations, immune microenvironment features, predicted drug sensitivity, single-cell differentiation dynamics, intercellular communication, and in silico virtual knockout perturbation (scTenifoldKnk). SRC emerged as the most robust hub gene after integration of WGCNA, PPI analysis, machine-learning feature selection, and survival screening. SRC was significantly upregulated in AML compared with normal controls and was independently associated with poor overall survival (HR = 1.231, p = 0.037). High SRC expression was linked to adverse ELN/FAB features, increased immune checkpoint expression, enrichment of inflammatory and immunoregulatory pathways, and a higher proportion of primitive leukemia-associated cell states. Single-cell analyses further suggested that SRC was enriched in CD34⁺ progenitor compartments, associated with altered cell–cell communication, and accompanied by distinct mutation and pathway profiles. Drug-response prediction and in silico network perturbation analysis further supported the potential biological and translational relevance of SRC-centered programs. SRC is a prognostically relevant and immune-associated hub linked to AML microenvironment remodeling, and may serve as a candidate biomarker and potential therapeutic target that warrants further experimental validation. Full article

Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment; however, durable responses occur in only a subset of patients, underscoring the need for robust predictive biomarkers. Serine/threonine kinase 11 (STK11) is an emerging biomarker that portends poor prognosis and predicts therapeutic resistance. Loss of STK11 disrupts AMPK signaling, leading to unchecked mTOR activation, metabolic reprogramming, angiogenesis, and epithelial–mesenchymal transition, fostering tumor progression and immune evasion. STK11 mutations frequently co-occur with KRAS and KEAP1 alterations, exhibit low PD-L1 expression, an immunosuppressive tumor microenvironment that leads to the development of PD-1/PD-L1 resistance. Clinical studies consistently demonstrate inferior outcomes with ICIs in STK11-mutant NSCLC, particularly in the presence of KRAS and KEAP1 co-mutations. Dual checkpoint inhibition combining PD-1/PD-L1 and CTLA-4 blockade shows promise in overcoming resistance, results remain inconsistent, and prospective trials are ongoing. Beyond immunotherapy, STK11 mutations confer poor outcomes across targeted therapies, including KRAS G12C inhibitors, with KEAP1 co-mutation serving as a strong negative predictor of efficacy. In this review we present an overview of STK11 function and its role in tumor biology, highlight the prognostic and predictive potential of STK11 mutations in the context of NSCLC treatment and summarize the emerging treatment strategies. Full article

It is well-known that immune checkpoint inhibitors (ICIs) can lead to uncommon but potentially life-threatening immune-related adverse events (irAEs) such as checkpoint-inhibitor pneumonitis (CIP). Early recognition, identification, and treatment are crucial with regard to decreasing toxicity from ICIs. However, there is a discrepancy in the incidence rates between the clinical trials and postmarketing studies. Several postmarketing studies have developed early detection methods and identified new risk factors in developing CIP. Thus, in this narrative review, we aim to review these incidence rates, early detection methods, and clinical risk factors for CIP in NSCLC patients, which could help to improve CIP diagnosis and management for enhanced NSCLC care. Major clinical trials and postmarketing studies of CIP incidence, early detection methods, and risk factors in NSCLC were reviewed. A wide array of potential risk factors has been implicated in the development of CIP in NSCLC, such as having preexisting interstitial lung disease, receiving PD-1 inhibitors, receiving combination ICI therapy instead of ICI monotherapy, lower pretreatment hemoglobin and albumin levels, increased baseline plasma IL-8 levels, and impaired baseline pulmonary function. Full article

The immunosuppression inherent to chronic lymphocytic leukemia (CLL) is the most frequent cause of morbidity and mortality associated with this pathology. Both the innate and adaptive immune responses exhibit marked functional alterations, with a bias towards a tolerant environment that favors the spread of the disease. This condition is reflected in increased risk of infections, immune-mediated cytopenias, and associated second malignancies. Knowledge of these alterations, both in the molecular pathways that modulate T cell activity in CLL (the T lymphocyte cytotoxic antigen-4 (CTLA-4) axis and programmed cell death 1 (PD-1)) and at the T cell immunoreceptor level, could be of interest as therapeutic targets in CLL. In this review, we will analyze the main consequences of this dysfunction and its management strategies. Full article

Steroid-sensitive cancers (e.g., breast, ovarian, uterine, and prostate cancers) are difficult to control and frequently metastasize to lymph nodes, bone, or lung. Although endocrine research has greatly advanced our identification of the direct roles of steroid sex hormones such as androgens and estrogens on tumor cells in promoting metastasis or recurrence (e.g., treatment with gonadotropin releasing hormone agonists/antagonists, aromatase inhibitors, and estrogen and androgen receptor antagonists), mechanistic insight regarding indirect effects of steroid hormones, including how the innate immune system responds to cancer and is influenced by steroid hormones, is lacking. Despite technological advances in engineering more robust adaptive immunity to combat tumor growth (e.g., CART or checkpoint inhibitors), there remains a relative lack of investigation into the role of innate immunity as a key defense system. Here we discuss recent studies that highlight the significance of neutrophils and their response to tumorigenic conditions with or without steroid hormones in animal models of cancer. We will describe relationships between steroid hormones and neutrophils, with a specific focus on neutrophil extracellular traps (NETs), and how these interactions modulate tumor growth and invasion. Together, these data indicate that combinatorial regulation of both innate and adaptive immunity in the context of tumorigenesis may improve outcomes in cancer therapies. Full article

Cutaneous melanoma is the most lethal form of skin cancer because of its aggressiveness, rapid metastasis, and high therapeutic resistance. The 2018 World Health Organization (WHO) classification emphasized that melanoma comprises distinct subtypes defined by cumulative sun damage, site of origin, and molecular characteristics, which explain differences in mutational burden, immunogenicity, and treatment response. Immunotherapy with anti-PD-1 therapy such as nivolumab and pembrolizumab changed the therapeutic landscape by restoring CD8+ T-cell activity and improving survival. Still, many patients show primary or acquired resistance influenced by low PD-L1 expression, loss of antigen presentation, tumor metabolic plasticity, and an immunosuppressive microenvironment. Mitochondria are central to this process. They regulate ATP generation through oxidative phosphorylation (OXPHOS), redox control, apoptosis, and the metabolic programming needed for T-cell activation. In the tumor microenvironment (TME), hypoxia, nutrient restriction, and PD-1 signaling reduce mitochondrial biogenesis, increase fission and reactive oxygen species (ROS) accumulation, and lead to exhaustion and impaired effector function. Moreover, tumor cells outcompete immune cells for key nutrients such as glucose and glutamine, while increased lactate production and extracellular acidosis further suppress mitochondrial respiration in T cells. Strategies to overcome resistance include restoring oxidative metabolism, activating PGC-1α, supplying metabolic substrates, and combining checkpoint blockade with inhibitors of glycolysis or glutaminolysis to enhance the immune response. Full article

Background: Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly aggressive pediatric central nervous system (CNS) malignancies. AT/RT of the lateral ventricle is an exceptionally rare subgroup, with only 11 reported cases. SMARCB1 inactivation is the primary molecular feature of AT/RT. Current consensus is to classify AT/RT based on methylation and molecular profiles into the following subgroups: AT/RT-TYR, AT/RT-SHH, AT/RT-MYC, and a potentially distinct SMARCA4-deficient subtype. AT/RT-MYC exhibits high levels of CD8⁺ tumor-infiltrating lymphocytes, indicating immunogenic potential. Case presentation: We report three pediatric cases presenting with intracranial hypertension and seizures. Diagnosis was confirmed via histopathology and molecular profiling. Interventions included gross total resection, chemotherapy, radiotherapy, and combined immune checkpoint inhibitors (pembrolizumab and ipilimumab). Outcomes varied from rapid progression to 3-year recurrence-free survival. A cohort of 14 pediatric patients with lateral ventricle AT/RT, comprising 3 institutional cases and 11 cases identified from the PubMed database, was evaluated through a narrative synthesis. Conclusions: These advancements highlight the crucial role of molecular subtyping in tailoring personalized treatments, including epigenetic modifiers and immune-based regimens. However, clinical validation is essential to establish standardized protocols. Integrating genomic, epigenetic, and immune microenvironment profiling may enhance risk assessment and treatment precision, ultimately improving survival and quality of life in pediatric patients. Full article

Background/Objectives: Nivolumab plus ipilimumab (IO–IO) provides durable clinical benefit in metastatic renal cell carcinoma (mRCC), yet long-term real-world data focusing on progression-free and treatment-free (PF–TF) survival remain limited. This study aimed to evaluate the long-term outcomes of IO–IO with a particular focus on the frequency and clinical characteristics of PF–TF. Methods: We retrospectively analyzed 63 patients with mRCC treated with first-line IO–IO across eight institutions with a minimum potential follow-up of five years. Progression-free survival (PFS), PFS2, and overall survival (OS) were assessed. PF–TF was defined as absence of disease progression and any cancer-directed therapy at the five-year landmark. Clinical and treatment-related factors were compared between patients with and without PF–TF. Results: The median PFS, PFS2, and OS were 7.5 (95% confidence interval [CI], 5.1–13.3), 26.2 (95% CI, 13.6–46.6), and 47.4 months (95% CI, 29.3–not reached), respectively. At 5 years, 11 patients (17%) achieved PF–TF. Baseline characteristics, IMDC risk classification, and peripheral blood biomarkers were not predictive of PF–TF. PF–TF was associated with the absence of bone metastases, presence of lymph node metastases, and occurrence of immune-related adverse events (irAEs), as well as the delayed onset of irAEs. No PF–TF patients required corticosteroid pulse therapy, and durable PF–TF was observed even after early treatment discontinuation due to adverse events. Conclusions: IO–IO demonstrated sustained long-term efficacy in real-world practice, with a subset achieving durable PF–TF. These findings highlight IO–IO as a strategy capable of providing long-term disease control with reduced treatment burden in selected patients with mRCC. Full article

Colorectal cancer (CRC) shows consistent sex-related differences in incidence, anatomic distribution, molecular subtype, immune context, and clinical outcome. However, these differences are often discussed through broad parallel themes such as hormones, genetics, or the microbiome, rather than through the biological settings in which sex meaningfully modifies tumor behavior. This review argues that sex is most informative in CRC when treated as a contextual modifier whose relevance emerges only after integrating tumor sidedness, mismatch repair status, oncogenic background, immune ecology, and age at onset. The clearest signals arise from interaction-based contexts, particularly when sex is interpreted together with tumor sidedness and dMMR/MSI-H or BRAF-linked disease states. Current evidence indicates that women are enriched for proximal or right-sided, microsatellite instability-high, mismatch repair-deficient, CpG island methylator phenotype-high, and BRAF-associated CRC, whereas men more often present with distal disease and a higher overall burden. Mechanistic studies further show that sex-related differences extend beyond hormone exposure to include KRAS–STAT4–KDM5D signaling, site-specific immune-checkpoint programs, metabolic phenotypes, epigenetic biomarker variation, and microbiota–hormone crosstalk. These effects are most evident in defined clinical niches, particularly right-sided CRC, mismatch repair-deficient disease, BRAF-mutated metastatic CRC, and early-onset CRC. A sex-aware, subtype-aware, and location-aware framework therefore offers a more clinically useful interpretation of CRC heterogeneity than descriptive male-versus-female comparisons alone. Full article

Cancer therapies are increasingly reliant on immunotherapeutic interventions; however, the persistent emergence of primary, adaptive, and acquired resistance severely limits durable clinical efficacy. Circular RNAs (circRNAs), distinguished by their extreme structural stability and covalently closed loops, have recently been established as potent orchestrators of this immune evasion. This review systematically synthesizes current advancements detailing how circRNAs undermine anti-tumor immunity across diverse malignancies. Specifically, we delineate their critical roles in post-transcriptionally upregulating immune checkpoint molecules (e.g., PD-L1), mediating intercellular immunosuppression via exosomal transfer, and metabolically reprogramming the tumor microenvironment to drive CD8+ T-cell exhaustion and macrophage polarization. Ultimately, we conclude that translating these molecular insights into clinical practice is paramount. Beyond serving as predictive biomarkers, engineering circRNA-targeted therapies and exploiting tumor-specific circRNAs to develop novel anti-tumor vaccines represent essential, paradigm-shifting strategies to definitively overcome immune checkpoint inhibitor resistance. Full article