Search Results (3,968)

Background/Objectives: Lung cancer remains the leading cause of cancer-related deaths globally, with non-small-cell lung cancer (NSCLC) accounting for most cases. Although advances in targeted therapies and immunotherapy have improved outcomes, long-term survival remains limited. This review aims to explore current immunotherapeutic strategies, the evolving role of therapeutic cancer vaccines, and the emerging potential of human papillomavirus-targeted interventions in lung cancer, particularly among non-smoker populations. Methods: A comprehensive search of the literature was conducted using PubMed, Scopus, and Web of Science databases to identify relevant articles published between 2015 and 2024. Studies focusing on immune checkpoint inhibitors, vaccine platforms, HPV-associated lung cancer, tumor microenvironment modulation, and novel delivery systems such as bacterial ghosts were included. Relevant clinical trials and preclinical studies were critically evaluated and synthesized. Results: Immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 have demonstrated clinical efficacy in NSCLC, yet their effectiveness is often limited by resistance mechanisms and lack of robust predictive biomarkers. Cancer vaccines, including peptide-based, mRNA, DNA, dendritic cell, and bacterial ghost platforms are emerging as complementary strategies to enhance antitumor immunity. Moreover, accumulating evidence suggests a potential association between high-risk HPV infection and lung cancer development, supporting the rationale for HPV-targeted vaccine strategies. Conclusions: Immunotherapy and therapeutic vaccination hold significant promise in reshaping lung cancer treatment. Advancements in vaccine design, delivery platforms like bacterial ghosts, and better understanding of HPV’s role in lung oncogenesis could support more effective, personalized immunotherapeutic approaches in the future. Full article

Malignant neoplasms, like non-small cell lung cancer (NSCLC), remain a major global health challenge. Lung cancer is the leading cause of cancer-related deaths worldwide, with over two million new cases and 1.8 million deaths annually. NSCLC accounts for approximately 85% of cases, underscoring its substantial public health impact. Advances in molecular biology have driven the development of new therapies beyond traditional treatments. Among them, mRNA-based immunoadjuvant therapies, like cancer vaccines, have emerged as promising utilities in NSCLC by triggering targeted immune responses. The aim of this paper is to review ongoing and completed studies on mRNA vaccines in NSCLC. The efficacy of mRNA vaccines in NSCLC relies on the identification of immunogenic tumor-specific antigens, frequently derived from genomic profiling databases. Completed clinical trials have assessed the safety and potential benefit of selected mRNA vaccines—such as CV9202—administered alone or in combination with radiotherapy or tyrosine kinase inhibitors. Ongoing studies are exploring the therapeutic potential of mRNA-based approaches targeting defined molecular alterations in NSCLC, particularly in conjunction with Programmed Death-Ligand 1 (PD-L1) immune checkpoint inhibitors to enhance antitumor immune responses. mRNA vaccines have emerged as a promising therapeutic option for NSCLC, with the potential to enhance immune responses and limit tumor progression, as demonstrated in ongoing clinical trials. They offer the possibility of personalized treatment with relatively few side effects. However, larger and long-term studies are required to fully confirm their safety and efficacy. Future research should aim to identify the most effective antigens, enhance stability, and refine delivery strategies to improve efficacy and personalization, while also addressing immune suppression within the tumor microenvironment. Full article

Immune checkpoint inhibitors (ICIs) display efficacy in non-small cell lung cancers (NSCLCs) with brain metastases (BMs) and studies suggest potential synergy with cranial radiation (CR). However, population-based evaluations of optimal time between ICI-CR combinations are limited in the US. Using SEER-Medicare database (2010–2019), we analyzed patients aged ≥65 years with NSCLC and BM receiving ICI-CR within 6 months of diagnosis, excluding those receiving targeted therapies. First treatment after diagnosis (ICI or CR) was defined as index treatment; followed by subsequent treatment. Findings were validated using an independent cohort from the TriNetX LIVE™ Platform. Patients were grouped by interval between the end of the index treatment and the start of the subsequent treatment: ≤15 days (n = 117), 16–30 days (n = 42), and >30 days (n = 77). Overall survival (OS) was measured from the start of the subsequent treatment until death, end of insurance coverage, or study end. Kaplan–Meier survival curves and multivariable Cox proportional hazards models estimated differences between groups. Among 236 patients, median OS was 134 days, 92 days, and 209 days, respectively. No significant OS differences were found across intervals. However, a survival benefit emerged approximately 300 days after follow-up when ICI was administered within 15 days of CR. These findings offer insight into treatment sequencing in NSCLC with BM and support further investigation in larger cohorts. Full article

Background/Objectives: Neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has prognostic value in non-small cell lung cancer (NSCLC), but its longitudinal performance in routine care is unclear. We evaluated baseline and 12-month changes in NLR and hemoglobin in a single-center, Eastern European cohort. Methods: In this retrospective study, 180 adults with histologically confirmed NSCLC, diagnosed May 2022–April 2024 at a Romanian tertiary center, were followed until 30 April 2025. Baseline demographics, tumor characteristics, molecular profiles, laboratory parameters, and treatments were extracted from electronic health records. Progression-free survival (PFS) was the primary endpoint, overall survival (OS) the secondary, analyzed using Kaplan–Meier curves and Cox proportional hazards models. An additional treatment-start-anchored sensitivity analysis in treated patients was conducted. Results: The cohort (median age 67.8 years, 68.9% stage IV) received chemo-immunotherapy (58.9%), immunotherapy (26.7%), chemotherapy (9.4%), or supportive care (5.0%). Median for PFS was 8.2 months and for OS 14.5 months. A high baseline NLR (≥3, 58.9%) increased progression risk (HR 1.60, 95% CI 1.10–2.32, p = 0.014), with a trend for worse OS (HR 1.45, 95% CI 0.99–2.12). A 12-month NLR increase (62.2%) further elevated progression risk (HR 1.52, 95% CI 1.05–2.20, p = 0.026). Low hemoglobin (<12 g/dL) had a non-significant effect (HR 1.38, 95% CI 0.97–1.96, p = 0.074). PD-L1 ≥ 50% and chemo-immunotherapy correlated with longer PFS. Findings were consistent in the treatment-start anchored sensitivity analysis. Conclusions: These exploratory findings suggest that inexpensive hematologic markers can complement clinical assessment in advanced-stage NSCLC; prospective multi-center validation is warranted. Full article

Afatinib and osimertinib are current treatment options for non-small cell lung cancer (NSCLC) patients with uncommon epidermal growth factor receptor (EGFR) mutations, although their efficacy is limited. To explore potentially effective drugs for these patients, we evaluated the efficacy of conventional EGFR tyrosine kinase inhibitors (TKIs) and novel third-generation (3G) TKIs using in vitro models. Ba/F3 cells transformed with each of the five most frequent uncommon EGFR mutations, Del18 (delE709_T710insD), E709K, G719A, S768I, and L861Q, were used. The growth inhibitory effects of five novel 3G-TKIs, almonertinib, lazertinib, furmonertinib, rezivertinib, and befotertinib, in addition to currently available TKIs, were evaluated. We also explored for secondary resistant mutations to afatinib or osimertinib and TKIs that can overcome these resistances. Afatinib was active against all uncommon EGFR mutations tested. The 3G-TKIs were all active against the L861Q mutation and were inactive against the S768I mutation. Furmonertinib and befotertinib showed efficacy against exon 18 mutations (Del18, E709K, and G719A). In the acquired resistance models to afatinib or osimertinib, we found T790M or a novel T725M secondary mutation, respectively, both of which could be overcome by lazertinib. However, some afatinib-resistant cells acquired V769L/M secondary mutations that were refractory to all EGFR-TKIs tested. In conclusion, afatinib exhibited broad activity and some 3G-TKIs showed promising efficacy in the front-line setting. Lazertinib is a potential second-line option after acquisition of resistance to afatinib or osimertinib. Full article

Brain metastases are a significant complication of non-small-cell lung cancer (NSCLC), contributing to high morbidity and mortality rates. The introduction of immune checkpoint inhibitors (ICIs) has opened new therapeutic avenues for patients with NSCLC, including those with brain metastases. However, the distinct microenvironment of the brain presents unique challenges to the effectiveness of these treatments. This review examines the mechanisms by which ICIs impact brain metastases from NSCLC, with particular focus on immune cell trafficking across the blood–brain barrier (BBB), tumor microenvironment modulation, and transcriptomic evolution of brain-tropic tumor clones. Unlike prior reviews, we integrate emerging data from single-cell and spatial transcriptomic studies, BBB disruption mechanisms, and the tumor-supportive role of brain-resident glia. We also critically evaluate key clinical trials and real-world evidence, highlighting differences in ICI efficacy across patient subgroups and therapeutic contexts. Additionally, we address the evolving role of surgical resection, stereotactic radiosurgery, and cerebrospinal-fluid-based biomarkers in optimizing ICI-based treatment strategies. This synthesis provides a comprehensive, mechanistic, and clinically relevant framework for improving outcomes in patients with NSCLC brain metastases treated with immunotherapy. Full article

The gut microbiome has emerged as a critical determinant of immune-checkpoint inhibitor (ICI) efficacy. A narrative review of 95 clinical studies (2015–2025) shows that patients with greater gut microbial diversity and relative enrichment of commensals such as Akkermansia, Ruminococcus, and other short-chain fatty acid producers experience longer progression-free and overall survival, particularly in melanoma and non-small-cell lung cancer. Broad-spectrum antibiotics given within 30 days of ICI initiation and over-the-counter mixed probiotics consistently correlate with poorer outcomes. Early phase I/II trials of responder-derived fecal microbiota transplantation in ICI-refractory melanoma achieved objective response rates of 20–40%, while pilot high-fiber or plant-forward dietary interventions improved immunologic surrogates such as CD8⁺ tumor infiltration. Machine-learning classifiers that integrate 16S or metagenomic profiles predict ICI response with an area under the ROC curve of 0.83–0.92. Methodological heterogeneity across sampling, sequencing, and clinical endpoints remains a barrier, underscoring the need for standardization and larger, well-powered trials. Full article

Purpose: Preclinical studies suggest that interleukin-1β (IL-1β) influences tumor behavior in non-small cell lung cancer (NSCLC). While the CANTOS trial demonstrated reduced lung cancer incidence with IL-1β inhibition, the CANOPY trials failed to show survival benefit when combined with chemoimmunotherapy. The role of IL-1β in NSCLC with oncogenic mutations remains unclear. We evaluated the prognostic and predictive significance of IL-1β expression across NSCLC subtypes. Methods: We analyzed 21,698 NSCLC tumors profiled by Caris Life Sciences using DNA and RNA next-generation sequencing. IL-1β expression was stratified into quartiles (Q1: lowest 25%, Q4: highest 25%). Real-world overall survival (OS) and time on treatment (TOT) were obtained from insurance claims. Statistical comparisons used Chi-square, Fisher’s exact, or Mann–Whitney U tests. Survival outcomes were assessed with Cox models. Results: Across unselected NSCLC patients, low IL-1β expression (Q1) was associated with modestly longer OS versus high expression (Q4) (median OS 19.5 vs. 17.4 months; HR 0.94; p < 0.0001). This effect was more pronounced in EGFR-mutant adenocarcinoma (36.7 vs. 27.2 months; HR 0.76; p < 0.001) and ALK fusion-positive NSCLC (53.0 vs. 35.2 months; HR 0.62; p = 0.002). In NSCLC without targetable mutations, IL-1β expression was not prognostic. In KRAS-mutant adenocarcinoma, high IL-1β expression was associated with modestly longer TOT on immunotherapy (7.4 vs. 6.4 months; HR 1.15; p = 0.041), but not OS. High IL-1β expression correlated positively with TP53 mutation, TMB-high, and PD-L1 expression and inversely with EGFR, KRAS, BRAF, ERBB2, KEAP1, and STK11 mutations. Conclusions: IL-1β expression is a potential prognostic and predictive biomarker in NSCLC, associated with survival outcomes in defined molecular subsets. These findings suggest that IL-1β-targeted strategies may be particularly relevant in EGFR- or ALK-altered tumors. Full article

Background: Single-agent pembrolizumab represents a standard of care in the first-line treatment of patients with metastatic non-small cell lung cancer (mNSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of ≥50%. Real-world evidence is of increasing importance in oncology, as clinical trial inclusion criteria may not be truly reflective of the patient population seen in daily clinical practice. Methods: We performed a prospective–retrospective single-center study including 121 patients who received pembrolizumab as a first-line therapy for mNSCLC with a PD-L1 TPS ≥ 50%. Our aims were to make a comparison with published clinical trial results by assessing the efficacy and safety of pembrolizumab monotherapy in our population. We collected patient demographics, clinical characteristics of the disease, and treatment outcomes, including efficacy and safety. Results: A total of 121 patients were included, with a median follow-up of 40.77 months. The median progression-free survival in the real world (rwPFS) was 20.73 months (95% CI 12.24–29.22), and the median overall survival (OS) was 29.30 months (95% CI 16.57–42.04). Immune-mediated adverse events (irAEs) occurred in 42% of patients, with serious events (grade 3 or more) occurring in 12%. ECOG PS 2, male gender, squamous histology, pleural and visceral metastases, and treatment with corticosteroids prior to initiation of pembrolizumab were found to be negative predictors for overall survival, while the occurrence of irAEs was the predictor of longer survival. Conclusions: This study provides further real-world insights into the efficacy of pembrolizumab in a heterogeneous patient population with advanced NSCLC in a single center in Serbia. It also confirmed the value of good ECOS PS and the occurrence of irAEs as predictors of favorable outcomes. Full article

Background/Objectives: KRAS mutations are among the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), with their impact on survival influenced by co-mutations. SMARCA4 mutations are increasingly associated with poor prognosis and can be classified as class 1 or class 2 mutations. This study evaluates the prognostic implications of KRAS and SMARCA4 mutations, including their co-mutations and their impact on NSCLC patients by utilizing real-world evidence. Methods: A retrospective analysis was conducted using the AACR GENIE Biopharma Collaborative (BPC) NSCLC 2.0 dataset. NSCLC patients with KRAS mutations, SMARCA4 mutations, or KRAS/SMARCA4 co-mutations were identified. Survival outcomes were assessed using univariate and multivariate Cox proportional hazards models, incorporating key clinical variables such as sex, race, smoking history, and stage. Results: Among 659 NSCLC patients with KRAS or SMARCA4 mutations analyzed, KRAS mutations were the most prevalent (79%, n = 518). SMARCA4 mutations were identified in 14% of cases (n = 95) across two classes. Six percent (n = 41) with class 1 mutations and 8% (n = 54) with class 2. Neither SMARCA4 class was associated with worse survival outcomes compared to KRAS-mutated patients (p = 0.438 & 0.720). Patients harboring KRAS/SMARCA4 class 1 co-mutations (3%, n = 18) had significantly worse overall survival compared to those with KRAS mutations alone (hazard ratio [HR] = 3.23, p < 0.001). In contrast, KRAS/SMARCA4 class 2 co-mutations (4%, n = 28) did not significantly impact survival compared to KRAS-mutated patients (HR = 1.34, p = 0.205). Conclusions: KRAS/SMARCA4 class 1 co-mutations are associated with significantly worse overall survival compared to KRAS-mutated NSCLC patients. Our multivariate analysis demonstrates the critical need to incorporate routine next-generation sequencing (NGS) testing in managing NSCLC patients at the time of metastatic diagnosis, with particular emphasis on identifying SMARCA4 mutation class as a potential prognostic biomarker in those with KRAS co-mutations. Full article

Background: Patients with early-stage (I–IIIA) resectable non-small cell lung cancer (NSCLC) often experience reduced physical activity (PA) after surgery. PA telecoaching may support a more active lifestyle, but evidence in this population is limited. Objective: To evaluate acceptability, feasibility, safety, and actual usage of an automated and manual PA telecoaching program following surgery for NSCLC. Methods: In this multicenter, single-blind study, patients received either an eight-week automated coaching program (ACP) with a customized smartphone app or a manual coaching program (MCP) with weekly phone calls from a coach. Both groups used an activity tracker, linked to their smartphone, to monitor steps and receive feedback. Primary outcomes included acceptability, feasibility, safety and usage, assessed via questionnaires and interviews. Secondary outcomes included objectively measured PA (accelerometry), functional exercise capacity (six-minute walk distance) and symptoms (dyspnea, fatigue) and quality of life, evaluated via questionnaires. Results: Nineteen patients (12 males; 68 ± 6 years; baseline daily steps 7820 ± 2799) were included. The majority (18/19) found the intervention enjoyable, and a minority (6/19) reported minor smartphone issues. All patients wore the activity tracker consistently. No adverse events occurred. The ACP required significantly less coach contact time compared to the MCP (25 ± 14 vs. 54 ± 15 min, p = 0.0003). No other differences in primary outcomes were observed between groups. Changes in secondary outcomes were limited in both groups. Conclusion: PA telecoaching is feasible, well accepted, and safe in patients with NSCLC post-surgery, with excellent activity tracker adherence. The ACP required less coach involvement. However, increasing PA remains challenging, and no conclusions can be made about the effectiveness of telecoaching. Future research should explore longer interventions in larger populations to assess efficacy and long-term outcomes. Full article

Background: LUAD, the most common subtype of lung cancer, particularly in non-smokers, is significantly influenced by air pollution from fine particulate matter (PM). One suspected method by which PM contributes to cancer progression is through angiogenesis, which promotes tumor growth and metastasis. This study was conducted to explore the impact of long-term PM exposure on the progression of LUAD, focusing on angiogenesis promotion. Methods: We conducted an integrative bioinformatics analysis incorporating epidemiological and transcriptomic datasets from public repositories (TCGA and GEO) to evaluate differential VEGFA expression in LUAD tissues and its relationship to regional PM exposure. In vitro and in vivo assays using PM-adapted NSCLC cell lines and murine xenograft models served as secondary confirmatory experiments supporting the computational results. Results: Epidemiological analysis revealed a strong positive correlation between long-term PM exposure and lung adenocarcinoma mortality across U.S. states (r = 0.7638, p < 0.0001), underscoring a population-level impact. Bioinformatics analysis identified a significant upregulation of VEGFA in NSCLC tumors from regions with high PM levels, with VEGFA overexpression also associated with poorer patient survival. Gene ontology and pathway enrichment analyses implicated angiogenesis-related processes. These findings were supported by experimental models, in which long-term PM exposure on human and murine LUAD cell lines (A549, H1299, and LLC) induced VEGFA and p-ERK overexpression. Furthermore, PM-exposed cells enhanced angiogenesis processes, as evidenced by increased endothelial cell tube formation and migration in vitro, and promoted tumor vascularization in a xenograft model. These pro-angiogenesis effects were abrogated following inhibition of the MAPK signaling pathway or blockade of VEGFA. Conclusions: Our findings reveal a compelling molecular link between PM exposure and NSCLC progression, centered on VEGFA-driven angiogenesis and urging the need to reduce ambient PM exposure to mitigate its oncogenic impact. Full article

Background/Objectives: Cancer-associated fibroblasts (CAFs) play a pivotal role in the tumor microenvironment. We conducted an analysis using RNA sequencing to identify specific markers for CAFs compared to normal fibroblasts (NFs) in non-small-cell carcinoma (NSCLC). Methods: CAFs and NFs were isolated and cultured from tumor tissues (primary tumor or metastatic lymph nodes) and matched non-tumor tissues, respectively. Bulk RNA sequencing was conducted on isolated CAFs and normal fibroblast NFs. Differential expressions, gene set enrichment, and CAF subpopulation prediction analyses were performed. Results: During the study period, 27 CAFs and 12 NFs were isolated and cultured from tumor and non-tumor tissues in patients with treatment-naïve NSCLC. Among them, 22 CAFs and 11 NFs were included in the RNA sequencing analysis. The 22 CAF samples consisted of 12 adenocarcinomas and 10 squamous cell carcinomas (SqCC), with 16 samples from the lungs and 6 samples from the lymph nodes. Notably, COL11A1, GREM1, CD36, and GAS6 showed a higher expression in CAFs than in NFs, whereas TNC and CXCL2 were more abundantly expressed in NFs. CD36 levels were elevated in CAFs from lymph nodes (LN-CAFs) compared with those from lung specimens (Lung-CAFs) and NFs. COL11A1 levels in Lung-CAFs surpassed those in LN-CAFs and NFs. Both GREM1 and GAS6 showed a strong expression in Lung-CAFs and LN-CAFs relative to NFs. CAFs exhibited features of the myofibroblast CAF subpopulation, whereas NFs displayed traits of the antigen-presenting CAF subtype. In the co-culture model of CAFs and THP-1 cells, the knockdown of GREM1 or GAS6 in CAFs significantly decreased the M2 marker expression in macrophages. Conclusions: In NSCLC, GREM1 and GAS6 can be valuable diagnostic targets for CAFs from primary tumors and metastatic sites; they warrant further study. Full article

Iron(III) (Fe(III)) complexes have recently emerged as safer alternatives to magnetic resonance imaging (MRI) contrast agents (CAs), reigniting interest in biomedical research. Although gadolinium Gd(III)-based contrast agents (CAs) have been widely used in MRI over the past four decades, their use in the current clinical routine is severely constrained due to concerns about high toxicity and environmental impact. Research is now focusing on synthesizing safer contrast agents with alternative paramagnetic ions like Fe(III) or Mn(II). MRI CAs with integrated potent therapeutic moieties may offer synergistic advantages over traditional contrast agents in clinical use. The study explored the use of salinomycin-ferrihydrite composites as possible effective ensembles of imaging and therapeutic units in the same molecule, evaluating their anticancer activity and influence on the signal in MRI. The composites were characterized using Mössbauer spectroscopy and ICP-MS for iron content determination. The in vitro relaxivity measurements in a high-field MR scanner demonstrated the potency of the composites as T₂ enhancers. The antitumor activity of one selected Sal-ferrihydrite composite was tested in three human cancer cell lines: A549 (non-small cell lung cancer); SW480 (colon cancer); and CH1/PA1 (ovarian teratocarcinoma) by the MTT cell viability assay. The new Sal-ferrihydrite composite showed a pronounced cytotoxicity in all three human cancers in line with enhanced signal in MRI, which makes it a promising candidate for future biomedical applications. The superior cytotoxic effect, together with the strong signal enhancement, makes these compounds promising candidates for further detailed investigations as future theranostic agents. Full article

Background and Objectives: Lung cancer (LC) remains a significant global health issue with poor prognosis. The COVID-19 pandemic has caused delays in cancer patient management worldwide. However, its impact on the incidence of LCs in Romania has not yet been discussed. We aimed to evaluate the impact of lockdown restrictions during the COVID-19 pandemic on new LC diagnoses in a Romanian cohort and the potential associations between demographic characteristics and histological features. Materials and Methods: This retrospective study analyzed 750 patients with lung tumors diagnosed in the Pathology Department, Mureș County Clinical Hospital, Romania, between 2018 and 2022. The target population was divided in two cohorts: pre-COVID-19 (1 January 2018–15 March 2020) and COVID-19 (16 March 2020–31 December 2022). Results: The temporal trend of LC diagnosis followed a descending pattern over the study period, with a significant 72% reduction (p < 0.001) in the first year of the COVID-19 pandemic (2020 vs. 2019). In terms of histology, several subtypes displayed a notable reduction in the COVID-19 cohort compared to the pre-pandemic period: squamous carcinoma (SQC) (p < 0.001), adenocarcinoma (ADK) (p < 0.001), and lung metastases (p = 0.0008). On the other hand, cases of non-small-cell lung carcinomas not otherwise specified (NSCLCs NOS) experienced a significant increase in the pandemic years (p = 0.0406). SQC was the most frequent subtype of LC and was significantly more frequent in men (p < 0.001, RR = 1.3004, 95% CI [1.1786–1.4347]). Furthermore, a notable shift in the male-to-female ratio was observed between the two cohorts, caused by a larger decrease in the incidence of LC among men compared to females in the COVID-19 period (p = 0.0002; pre-COVID-19 M/F = 4/1 versus COVID-19 M/F = 2/1). Conclusions: COVID-19-related restrictions led to a significant drop in new LC diagnoses during the first year of the pandemic, which was followed by a slight upward trend in the subsequent years. Additionally, the sharp decline in the number of cases among men narrowed the gender gap in LC patients. Full article