This study aimed to identify latent profiles of fear of cancer recurrence (FCR) among patients with early-stage non-small cell lung cancer (NSCLC) and examine the associated factors.

A cross-sectional survey was conducted with 677 patients with early-stage NSCLC who underwent surgical treatment at a tier-three cancer hospital in Beijing between January 2022 and August 2023. Data collection included demographic variables and assessments using the Fear of Progression Questionnaire-Short Form (FoP-Q-SF), Herth Hope Index (HHI), and Social Support Rating Scale (SSRS). Latent profile analysis was employed to classify FCR levels and identify influencing factors.

Three distinct FCR profiles emerged: "low FCR" (27.6%), "moderate FCR" (66.2%), and "high FCR" (6.2%). Independent risk factors for moderate FCR included individuals aged 36-60 years (odds ratio [OR] ​= ​1.871, 95% confidence interval [CI] 1.208-2.899) and a household income below 5000 yuan (OR ​= ​1.86, 95% CI 1.059-3.267). Protective factors for moderate FCR included lower levels of education (OR ​= ​0.505, 95% CI 0.283-0.902), religious beliefs (OR ​= ​0.355, 95% CI 0.152-0.833), and smoking (OR ​= ​0.461, 95% CI 0.284-0.747). High FCR was strongly associated with being 36-60 years old, lower HHI scores (OR ​= ​11.055, 95% CI 4.441-27.522), and poor social support (OR ​= ​3.392, 95% CI 1.385-8.308).

FCR among patients with early-stage NSCLC can be categorized into distinct profiles, with specific demographic and psychosocial factors influencing severity. Tailored nursing interventions addressing varying FCR levels are critical to improving patient care and psychological well-being.

Despite significant progress in diagnostic and therapeutic modalities, lung adenocarcinoma (LUAD) still exhibits a high recurrence risk and a low 5-year survival rate. Reliable prognostic signatures are imperative for risk stratification in LUAD patients. This study encompassed 2740 patients from 23 LUAD cohorts, including one single-cell RNA sequencing (scRNA-seq) dataset, five bulk RNA-seq datasets, and 17 microarray datasets. Using scRNA-seq dataset, we defined a group of epithelial-specific transcription factors significantly over-represented in the epithelial-to-mesenchymal transition (EMT) gene set (enrichment ratio [ER] = 5.80, Fisher's exact test p < .001), and the corresponding target genes were significantly enriched in the cancer driver gene set (ER = 2.74, p < .001), indicating of their crucial roles in the EMT process and tumor progression. We constructed a single-cell gene pairs (scGPS) signature, composed of 3521 gene pairs derived from the epithelial cell-specific transcription factor regulatory network, to predict overall survival (OS) of LUAD. High-risk patients identified by scGPS in the discovery cohort exhibited significantly worse OS compared to low-risk patients (Hazard ratio [HR] = 1.78, 95% CI: 1.29-2.46, log-rank p = 1.80 × 10-4). The scGPS outperformed other established gene signatures and demonstrated robust prognostic stratification across various independent datasets, including microarray data and even early-stage LUAD patients. It remained an independent prognostic factor after adjusting for clinical and pathologic factors. In addition, combining scGPS with tumor stage further enhanced prognostic accuracy compared to using stage alone. The scGPS signature offers individualized prognosis estimations, showing significant potential for practical application in clinical settings.

Immune checkpoint inhibitors (ICIs) are potent and precise therapies for various cancer types, significantly improving survival rates in patients who respond positively to them. However, only a minority of patients benefit from ICI treatments.

Identifying ICI responders before treatment could greatly conserve medical resources, minimize potential drug side effects, and expedite the search for alternative therapies. Our goal is to introduce a novel deep-learning method to predict ICI treatment responses in cancer patients.

The proposed deep-learning framework leverages graph neural network and biological pathway knowledge. We trained and tested our method using ICI-treated patients' data from several clinical trials covering melanoma, gastric cancer, and bladder cancer.

Our results demonstrate that this predictive model outperforms current state-of-the-art methods and tumor microenvironment-based predictors. Additionally, the model quantifies the importance of pathways, pathway interactions, and genes in its predictions. A web server for IRnet has been developed and deployed, providing broad accessibility to users at https://irnet.missouri.edu.

IRnet is a competitive tool for predicting patient responses to immunotherapy, specifically ICIs. Its interpretability also offers valuable insights into the mechanisms underlying ICI treatments.

Lung cancer remains the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85 % of cases. Despite advancements in diagnostics and therapies, tumor metastasis and drug-resistant recurrence present significant clinical challenges. This study evaluates the prognostic role of ADH1B in lung adenocarcinoma (LUAD) metastasis and recurrence. Analysis of tissue samples from 46 LUAD patients revealed that lower ADH1B expression correlates with increased metastasis and poorer overall survival. Kaplan-Meier survival analysis demonstrated that elevated ADH1B levels are significantly associated with longer overall survival and recurrence-free survival. In vitro experiments indicated that ADH1B overexpression inhibits proliferation, migration, and invasion in A549 and H1299 cell lines. Additionally, ADH1B expression was negatively correlated with tumor stemness markers, indicating its role in suppressing stem cell characteristics. Mechanistically, ADH1B activates the cAMP/PKA/CREB1 signaling pathway, enhancing SOX1 expression and inhibiting the ERK pathway, which contributes to reduced tumor stemness. In vivo studies confirmed that ADH1B overexpression decreases stem cell populations and tumor growth in xenograft models. Our findings suggest that ADH1B functions as a critical regulator of LUAD progression, with its low expression acting as a marker of poor prognosis while promoting metastasis and tumor stemness. This research identifies ADH1B as a potential therapeutic target, offering novel strategies to address the challenges of metastasis and recurrence in LUAD.

Scanning ion conductance microscopy (SICM) is a noninvasive topographic mapping technique used in imaging live cells, unlike electron microscopy and certain applications of fluorescence microscopy, which can disrupt cell integrity. In this study, we used SICM to track the morphological changes of the same A549 cells to uncover the cell-to-cell heterogeneity in their response to the drug. We found that toyocamycin (TOY) induced rapid reorganization of the actin cytoskeleton in A549 cells, causing them to become circular, irregular, or ellipsoidal in shape. Mapping of the dynamic changes in morphology revealed membrane blebbing and a significant decrease in volume over time. Using high-throughput SICM, we mapped the morphology of multiple single cells treated with TOY, which revealed that A549 showed characteristics of apoptosis and necrosis. The drug treatment does not significantly change the average root-mean-square (RMS) roughness of the cells. However, the drug leads to an increase in membrane height, possibly indicating early apoptotic changes. Plotting the individual RMS roughness of the cells showed a cell with an increase in roughness and the presence of pores, which is also an indication of necrosis behavior. Our results demonstrate that SICM is an effective technique for revealing the evolution of heterogeneity in single cells in their responses to anticancer drugs over time.

The mechanistic relationship between respiratory disorders and brain function remains poorly understood, despite growing evidence of cognitive and neurological manifestations in respiratory diseases. We aim to identify whether specific brain network connectivity patterns causally influence respiratory disease susceptibility, while respiratory conditions might reciprocally affect brain network architecture.

We performed bidirectional Mendelian randomization analyses using genome-wide association studies (GWAS) of brain network connectivity from UK Biobank resting-state functional MRI data (N=31,453) and GWAS data from ten major respiratory conditions: chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sleep apnea syndrome (SAS), lung squamous carcinoma (LUSC), lung adenocarcinoma (LUAD), small cell lung carcinoma (SCLC), hospitalized COVID-19, very severe COVID-19, and bronchiectasis. Five MR methods, inverse variance weighted (IVW) with multiplicative random-effect model, weighted median, weighted mode, MR Egger, and MR-robust adjusted profile score (MR-RAPS) were employed to ensure causal inference.

In forward analysis, five respiratory disorders - asthma, IPF, SAS, LUSC, and very severe COVID-19 - showed significant causal associations (p<1.31×10-4) with 11 rs-fMRI phenotypes, spanning multiple brain networks including the central executive, subcortical-cerebellum, motor, limbic, attention, salience, visual, and default mode networks. In reverse analysis, twelve brain functional networks demonstrated genetic associations with eight respiratory conditions (COPD, asthma, IPF, SAS, LUSC, SCLC, hospitalized COVID-19, and very severe COVID-19), predominantly involving attention, salience, default mode, visual, and central executive networks.

Our study provides preliminary genetic evidence suggesting potential causal relationships between brain network connectivity and respiratory disorders, contributing to our understanding of the lung-brain axis. While the identification of disease-specific network alterations offers promising insights, further clinical validation is needed before these findings can be translated into therapeutic interventions.

LUAD, a prevalent lung cancer with high mortality, has seen increased focus on molecular targeted therapies due to patient heterogeneity. Among these prospects, dystrophin-associated protein 2 (DRP2), a critical component of the dystrophin complex, underpins membrane-associated structures vital for intercellular interactions in vertebrates. Aberrations in DRP2 function have been linked to the occurrence and development of multiple diseases, prompting an inquiry into its potential link with LUAD progression. To delve into the potential roles of DRP2 in LUAD, we initiated a comprehensive investigation. First, we analyzed DRP2 expression patterns in LUAD using bioinformatics tools. This was subsequently validated through immunohistochemical staining, quantitative PCR, and Western blot analyses. Furthermore, we assessed the functional implications of DRP2 in LUAD cells, both in vitro and in vivo, utilizing assays such as cell cycle analysis, CCK-8 proliferation assay, Colony formation assay EdU incorporation, Transwell migration test, scratch wound healing assay, flow cytometry, and mouse models for tumor xenograft and metastasis. Results showed a strong correlation between high DRP2 expression in LUAD and poorer survival. Notably, DRP2 knockdown accelerated LUAD progression via the EMT pathway. These findings highlight DRP2's crucial role in LUAD and its potential as a therapeutic target.

Recent studies indicate that Secretogranin V (SCG5) is aberrantly expressed in various cancers and may be linked to tumor progression and prognosis. This study aims to evaluate the potential of SCG5 as a prognostic biomarker for non-small cell lung cancer (NSCLC). We employed a combination of bioinformatics analysis, Western blotting, and immunofluorescence techniques to investigate the role of SCG5 in NSCLC. A comprehensive analysis of TCGA and GEO pan-cancer datasets revealed a consistent upregulation of SCG5 across multiple cancer types. In NSCLC, SCG5 expression was significantly higher in tumor tissues compared to normal lung tissues (p < 0.001). Kaplan-Meier survival analysis demonstrated that patients with elevated SCG5 expression exhibited lower overall survival rates, suggesting a strong association with poor prognosis. Univariate and multivariate COX regression analyses, conducted on both TCGA cases and our collected patient data, confirmed SCG5 as an independent prognostic factor for NSCLC. Furthermore, immune infiltration analysis indicated a significant correlation between SCG5 expression and various immune cell subpopulations, underscoring its potential role as a biomarker for adverse outcomes. Western blot analysis further validated the elevated levels of SCG5 in NSCLC tissues and cell lines compared to their normal counterparts. Based on our findings, we hypothesize that SCG5 may serve as a valuable biomarker for predicting the prognosis of non-small cell lung cancer, thereby guiding future research in the fields of diagnosis, progression, therapy, and prognosis of NSCLC.

Lung cancer, a major cause of cancer-related mortality, has limited therapeutic options, especially for advanced cases. Ferroptosis, an iron-dependent form of cell death, is a potential therapeutic strategy for this disease; however, resistance mechanisms in the tumor microenvironment impede its effectiveness. Therefore, in this study, we aimed to investigate the efficacy of sulfasalazine (SAS), a ferroptosis inducer, and auranofin (AUR), a Food and Drug Administration-approved anti-inflammatory agent, combination to counteract ferroptosis resistance in lung cancer. SAS induced ferroptosis in vitro; however, its efficacy in vivo was limited, possibly because of factors, such as nutrient deprivation and high cell density, in the microenvironment that suppressed the activities of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key regulators of ferroptosis resistance. Screening of 2483 drugs revealed AUR as a compound resensitizing the YAP/TAZ-deficient lung cancer cells to ferroptosis. Moreover, SAS and AUR combination significantly enhanced lipid peroxidation and reactive oxygen species accumulation, further driving ferroptosis in cells. This combination effectively inhibited tumor growth and enhanced survival in a murine lung cancer model. Overall, our findings suggest that AUR potentiates ferroptosis-based therapies, serving as an effective candidate to overcome ferroptosis resistance in lung cancer.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has been recognized as a promising target for cancer immunotherapy. Although various STING agonists have been developed, their clinical applications are still severely impeded by various issues, such as non-specific accumulation, adverse effects, rapid clearance, etc. In recent years, the emergence of nanomaterials has profoundly revolutionized STING agonists delivery, which promote tumor-targeted delivery, boost the immunotherapeutic effects and reduce systemic toxicity of STING agonists. In particular, polymer nanomaterials possess inherent advantages including controllable structure, tunable function and degradability. These properties afford them the capacity to serve as delivery vehicles for small-molecule STING agonists. Furthermore, the superior characteristics of polymer nanomaterials can enable their utilization as a novel STING agonist to stimulate anti-tumor immunity. In this review, the molecular mechanisms of cGAS-STING pathway activation are discussed. The recent development of small-molecules STING agonists is described. Then polymer nanomaterials are discussed as carriers for STING agonists in cancer immunotherapy, including polymersomes, polymer micelles, polymer capsules, and polymer nanogels. Additionally, polymer nanomaterials are identified as a novel class of STING agonists for efficient cancer immunotherapy, encompassing both polymer materials and polymer-STING agonists conjugates. The review also presents the combination of polymer-based cGAS-STING immunotherapy with chemotherapy, radiotherapy, phototherapy (both photodynamic and photothermal), chemodynamic therapy, and other therapeutic strategies. Furthermore, the discussion highlights recent advancements targeting the cGAS-STING pathway in clinically approved polymer nanomaterials and corresponding potent innovations. Finally, the potential challenges and perspectives of polymer nanomaterials for activating cGAS-STING pathway are outlined, emphasizing the critical scientific issue and hoping to offer guidance for their clinical translation.

Immunotherapy based on programmed cell death protein receptor 1 and its ligand (PD-1/PD-L1) has become an important method for treating non-small cell lung cancer (NSCLC). Peptide-based and nanobody-based PET tracers offer potential advantages in PD-L1 detection, yet their comparative tumor uptake and biodistribution remain unclear. This study aimed to evaluate and compare [68Ga]Ga-DOTA-WL12 (a peptide-based tracer) and [68Ga]Ga-NOTA-RW102 (a nanobody-based tracer) in assessing PD-L1 expression in primary and metastatic NSCLC, providing insights for future radiotracer design and theranostic applications.

Ten patients diagnosed with NSCLC underwent [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT scans, with four of these patients also receiving [18F]FDG PET/CT scans. The tracer uptakes, quantified by maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and target-to-background ratio (TBR), were compared between [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT.

DOTA-WL12 and NOTA-RW102 exhibited favorable binding affinities with PD-L1, with equilibrium dissociation constant (KD) values of 0.2 nM and 0.0047 nM, respectively. Subsequent human studies revealed significant variations (P < 0.05) in the uptake of [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 across the liver (SUVmean: 20.43 ± 4.26 vs. 6.12 ± 1.36, p = 0.015), kidney (SUVmean: 2.40 ± 0.34 vs. 22.37 ± 2.88, P = 0.015), spleen (SUVmean: 2.44 ± 0.67 vs. 18.49 ± 3.90, P = 0.015), and lung background (SUVmean: 0.18 ± 0.12 vs. 1.09 ± 0.29, P = 0.015). Meanwhile, we found that the correlation between SUVmax and PD-L1 TPS was significantly stronger with [68Ga]Ga-DOTA-WL12 compared to [68Ga]Ga-NOTA-RW102 (P < 0.0001, r = 0.9471 vs. P = 0.0241, r = 0.5235).

The uptake of peptide-based [68Ga]Ga-DOTA-WL12 was more strongly correlated with PD-L1 TPS in primary and metastatic tumor lesions compared to [68Ga]Ga-NOTA-RW102. They also displayed different distribution, suggesting that peptide-based and nanobody-based radiotracers may have different clinical implications, particularly in radiotherapy.

Accurate preoperative recurrence prediction for non-small cell lung cancer (NSCLC) is a challenging issue in the medical field. Existing studies primarily conduct image and molecular analyses independently or directly fuse multimodal information through radiomics and genomics, which fail to fully exploit and effectively utilize the highly heterogeneous cross-modal information at different levels and model the complex relationships between modalities, resulting in poor fusion performance and becoming the bottleneck of precise recurrence prediction. To address these limitations, we propose a novel unified framework, the Self-and-Mutual Attention (SAMA) Network, designed to efficiently fuse and utilize macroscopic CT images and microscopic gene data for precise NSCLC recurrence prediction, integrating handcrafted features, deep features, and gene features. Specifically, we design a Self-and-Mutual Attention Module that performs three-stage fusion: the self-enhancement stage enhances modality-specific features; the gene-guided and CT-guided cross-modality fusion stages perform bidirectional cross-guidance on the self-enhanced features, complementing and refining each modality, enhancing heterogeneous feature expression; and the optimized feature aggregation stage ensures the refined interactive features for precise prediction. Extensive experiments on both publicly available datasets from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) demonstrate that our method achieves state-of-the-art performance and exhibits broad applicability to various cancers.

KRAS mutation is one of the most common mutational events in non-small-cell lung cancer (NSCLC). However, due to the complex signaling pathways and high biological heterogeneity of KRAS-mutant NSCLC, the current clinical treatment for patients with KRAS mutations still faces many difficulties. The oncogenic effector in KRAS-mutant NSCLC was screened using GEO data sets. CCK-8, colony formation, transwell, and flow cytometry were conducted to assess the malignant phenotype of KRAS-mutant NSCLC cells. The indicators intracellular Fe2+, ROS, GSH, and MDA levels were employed to reflect the ferroptosis of cells. The mechanism of myeloma overexpressed (MYEOV) in KRAS-mutant NSCLC was explored from the perspective of noncoding RNA (ncRNA) and validated by rescue experiments. MYEOV presented a high expression trend in KRAS-mutant NSCLC specimens. MYEOV silencing effectively repressed the malignant phenotype and promoted ferroptosis of NSCLC cells carrying KRAS mutations. Based on bioinformation analysis and a series of rescue experiments, we established the HHLA3/miR-139-5p/MYEOV regulatory network in KRAS-mutant NSCLC cells and disclosed that HHLA3 served as a molecular sponge for miR-139-5p to regulate MYEOV expression. The mechanism of MYEOV and its ncRNA network affecting the progression of KRAS-mutant NSCLC revealed in this study intends to provide a theoretical basis for KRAS-mutant NSCLC treatment.

Non-small cell lung cancer (NSCLC) shows limited therapeutic response to vinorelbine and carboplatin. Combining these drugs with an antifibrotic drug may enhance their antitumor effect. Pirfenidone is an antifibrotic drug whose antitumor activity has been described in different types of cancer. This work aimed to perform preclinical studies on the combination of pirfenidone with vinorelbine, or with vinorelbine plus carboplatin, in NSCLC. Our data revealed that pirfenidone sensitized three NSCLC cell lines to vinorelbine by reducing cell growth, viability and proliferation, inducing alterations in the cell cycle profile, and increasing cell death (%). Importantly, pirfenidone increased the sensitivity of the three NSCLC cell lines to the combined treatment of vinorelbine plus carboplatin. This combined drug treatment (triplet) did not induce cytotoxicity against non-tumorigenic cells. Notably, the triplet drug combination significantly reduced the growth and proliferation of A-549 xenografts in nude mice, as also reduced vimentin and collagen expression. Most interestingly, the triplet treatment exhibited a safer toxicological profile than the doublet (vinorelbine plus carboplatin) currently applied in the clinical practice. Altogether, these preclinical data support the possibility of repurposing pirfenidone in combination with vinorelbine or with vinorelbine plus carboplatin for NSCLC perioperative treatment, improving therapeutic efficacy while reducing toxicity.

Tumor-associated macrophages (TAMs) are a type of highly plastic immune cells in the tumor microenvironment (TME), which can be classified into two main phenotypes: classical activated M1 macrophages and alternatively activated M2 macrophages. As previously reported, M2-polarized TAMs play critical role in promoting the progression of non-small cell lung cancer (NSCLC) via secreting exosomes, but the detailed mechanisms are still largely unknown. In the present study, the THP-1 monocytes were sequentially induced into M0 and M2-polarized macrophages, and the exosomes were obtained from M0 (M0-exos) and M2 (M2-exos) polarized macrophages, respectively, and co-cultured with NSCLC cells (H1299 and A549) to establish the exosomes-cell co-culture system in vitro. As it was determined by MTT assay, RT-qPCR and Transwell assay, in contrast with the M0-exos, M2-exos significantly promoted cell proliferation, migration and epithelial-mesenchymal transition (EMT) process in NSCLC cells. Next, through screening the contents in the exosomes, it was verified that miR-155-5p was especially enriched in the M2-exos, and M2-exos enhanced cancer aggressiveness and tumorigenesis in in vitro NSCLC cells and in vivo xenograft tumor-bearing mice models via delivering miR-155-5p. The detailed molecular mechanisms were subsequently elucidated, and it was found that miR-155-5p bound with HuR to increase the stability and expression levels of VEGFR2, which further activated the tumor-promoting PI3K/Akt/mTOR signal pathway, and M2-exos-enhanced cancer progression in NSCLC cells were apparently suppressed by downregulating VEGFR2 and PI3K inhibitor LY294002 co-treatment. Taken together, M2-polarized TAMs secreted miR-155-5p-containing exosomes to enhanced cancer aggressiveness of NSCLC by activating the VEGFR2/PI3K/Akt/mTOR pathway in a HuR-dependent manner.

This study aims to evaluate cytokines as a prognostic biomarker in patients with advanced non-small cell lung cancer (aNSCLC) undergoing immunotherapy.

A comprehensive analysis was conducted to assess the prognostic significance of sCD14 and other cytokines in aNSCLC patients receiving immune checkpoint inhibitors (ICIs) using flow fluorescence. A discovery cohort (n = 42) was used to evaluate the differential expression of 41 cytokines between durable clinical benefit (DCB) and no durable benefit (NDB) groups in Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS). The prognostic value was further validated in multiple independent cohorts, including plasma protein measurements (n = 109), multiplex immunofluorescence (mIF) (n = 22), and messenger RNA datasets (n = 403) of NSCLC in CHCAMS.

In the discovery cohort, 7 cytokines (CD14, CCL27, IL-17 A, EGF, TNFR1, GFAP, CHI3L1) exhibited differential expression between the DCB and NDB groups. Among these, CD14, CCL27, IL-17 A, and TNFR1 were significantly elevated in the DCB group, while EGF, CHI3L1, and CCL5 were higher in the NDB group. CD14 showed a high area under the curve (AUC = 0.84) for predicting clinical benefit. Functional enrichment analysis indicated that these cytokines are involved in key immune pathways, including the inflammatory response and MAPK signaling. Univariate COX for progression-free survival (PFS) analysis demonstrated prognostic value for CD14 (p < 0.001, HR = 0.054 [0.014-0.219]), CCL27 (p < 0.001, HR = 0.054 [0.015-0.196]), IL-17 A (p < 0.001, HR = 0.110 [0.041-0.298]), and CCL5 (p < 0.05, HR = 2.387 [1.023-5.570]). Validation in the CHCAMS cohort confirmed that CD14 expression, measured via mIF, was a predictor of PFS (p < 0.05). Furthermore, high CD14 expression was consistently associated with superior PFS across multiple external datasets (GSE126044, GSE135222, GSE136961, and GSE218989). CD14 expression was found to be elevated in various normal tissue types, particularly in lung adenocarcinoma and lung squamous cell carcinoma, compared to tumors, indicating its potential role in immune surveillance.

sCD14 is a promising prognostic biomarker for aNSCLC patients undergoing immunotherapy. Elevated plasma sCD14 levels are associated with improved PFS and a favorable immune response.

The objective of this study was to investigate the clinical and genetic characteristics and clinical relevance of HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients.

This prospective study analyzed 51 NSCLC patients with HER2 mutations, identified via next-generation sequencing (NGS) of tissue, blood, cerebrospinal fluid, or pleural effusion samples. Patients were grouped based on the presence of exon 20 mutations (exon 20 vs. non-exon 20) and further divided based on whether they had received prior anti-tumor treatments (baseline vs. non-baseline). Clinical and genetic data, treatment responses were analyzed. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods and compared with log-rank tests. Gene ontology (GO) analysis was performed to uncover the biological significance of the mutated genes.

In a cohort of 651 NSCLC patients, 51 (7.83%) harbored HER2 alterations, including 20 (3.08%) with exon 20 mutations. The median age of the HER2-altered subgroup was 58.5 years. Adenocarcinoma was the most prevalent subtype (96.1%), and most patients presented at stage IV (72.5%). The most common metastatic sites were the lungs (68.6%), lymph nodes (52.9%), and brain (43.1%). Among the HER2 mutated patients, 20 (39.3%) had exon 20 mutations. Exon 20 mutations were more prevalent in the non-baseline group (55.0% vs. 29.0%, P = 0.049) and males (75.0%, P = 0.025). These mutations were associated with a higher rate of metastasis to the lungs, lymph nodes (P < 0.001). Patients with exon 20 mutations demonstrated poorer overall survival (OS) outcomes (P = 0.048). No significant differences were observed in age, smoking history, histological subtype, or TNM stage at diagnosis between groups. The majority of exon 20 mutations were in-frame indel mutations (92.0%), with the most common specific mutation being p.Y772_A775dup (70%). Gene Ontology (GO) analysis linked exon 20 mutations to unregulated protein kinase activity and anoikis.

Our study found that NSCLC patients with HER2 exon 20 oncogenic variants have a higher risk of metastasis and drug resistance, leading to worse outcomes than non-exon 20 mutations. This highlights the urgent need for targeted therapies aimed at exon 20 insertions to improve survival and treatment outcomes in this subgroup.

In situ radiotherapy is the most successful cytotoxic therapy available for the treatment of solid tumors, while high-dose radiotherapy per fraction is not yet widely and reliably used. To some extent, the major considerations of the disappointing results are on the risk of high-dose irradiation-induced damage to the surrounding normal tissues and the difficulty in distant metastasis control. To break these restraints, a gelatinase-responsive amphiphilic methoxypolyethyleneglycol-PVGLIG-polycaprolactone (mPEG-PVGLIG-PCL) nanoparticles' loading verteporfin (N@VP), a special photosensitizer that can also be excited by X-rays to produce cytotoxic singlet oxygen and greatly enhance radiotherapy efficacy, is prepared in this study. Herein, it is shown that the formed N@VP combined with conventional-dose radiation therapy (RT, 2 Gy (gray, a radiation dose unit)) can realize an antitumor effect no less than high-dose RT (8 Gy) and minimize radiation dose necessary to achieve local tumor control. Moreover, this radiosensitive nanosystem can exert excellent systemic antitumor immunity and abscopal effect, providing a preferable "in situ vaccine" strategy based on conventional-dose RT to achieve efficient systemic management of distant tumor metastasis. When combined with immunotherapy, this novel strategy for radiosensitization results in better immunotherapy sensitivity by stimulating significant immunogenic tumor cell death and synergistic antitumor immune responses.

Realizing the point-of-care tumor markers biodetection with good convenience and high sensitivity possesses great significance for prompting cancer monitoring and screening in biomedical study field. Herein, the quantum dots luminescence and microfluidic biochip with machine vision algorithm-based intelligent biosensing platform have been designed and manufactured for point-of-care tumor markers diagnostics. The employed quantum dots with excellent photoluminescent performance are modified with specific antibody as the optical labeling agents for the designed sandwich structure immunoassay. The corresponding biosensing investigations of the designed biodetection platform illustrate several advantages involving high sensitivity (~ 0.021 ng mL-1), outstanding accessibility, and great integrability. Moreover, related test results of human-sourced artificial saliva samples demonstrate better detection capabilities compared with commercially utilized rapid test strips. Combining these infusive abilities, our elaborate biosensing platform is expected to exhibit potential applications for the future point-of-care tumor markers diagnostic area.

Recent research has highlighted the significance of circular RNAs (circRNAs) as pivotal regulators in the progression of tumors and the therapeutic response in non-small cell lung cancer (NSCLC). These circRNAs function through a sponge mechanism, interacting with microRNAs (miRNAs) to modulate mRNA expression levels. Nevertheless, the precise role of the circRNA-miRNA-mRNA regulatory network in immune regulation within lung adenocarcinoma (LUAD) remains inadequately understood.

We utilized microarray datasets from the GEO NCBI database (GSE101586) to identify differentially expressed circRNAs (DEcircRNAs) in LUAD. CircBank was employed to predict the target miRNAs of DEcircRNAs, which were subsequently intersected with miRNAs from the GSE36681 database. The identified miRNAs were then predicted to target mRNAs using miRDB and miWalk, and intersections with immune-related genes from the IMMPORT database were analyzed. Protein-protein interaction (PPI) networks were constructed using Cytoscape software. The DAVID functional annotation tool was utilized to explore potential biological processes, molecular functions, and KEGG pathways associated with LUAD. Gene expression and Kaplan-Meier survival analyses were conducted to establish a key regulatory network and to assess immune cell infiltration and Pearson correlation for significant target genes. Finally, we selected the most significantly upregulated circRNA with differential expression for validation through in vitro experiments.

Our analysis identified a total of 7 upregulated and 42 downregulated circRNAs, along with 10 significant miRNAs and 20 target mRNAs. KEGG enrichment analysis indicated that these components are primarily enriched in the ErbB signaling pathway. Furthermore, Gene Ontology (GO) analysis revealed significant enrichment in responses to organic substances, cytokine-mediated signaling pathways, cellular responses to cytokines, responses to chemical stimuli, steroid hormone receptor activity, ErbB-3 class receptor binding, oxysterol binding, signal receptor activity, and molecular transducer activity. Notable core mRNAs identified included OAS1, VIPR1, and PIK3R1. Subsequently, we constructed a regulatory network comprising 6 DEcircRNAs, 3 DEmiRNAs, and 3 DEmRNAs. Through ssGSEA and CIBERSORT analyses, we observed significant differences in immune cell infiltration levels between the NSCLC cohort and the control group. Knocking down the expression of hsa_circ_0079557 significantly inhibited the viability, proliferation, migration, and invasion of LUAD cells.

We have established a circRNA-miRNA-mRNA regulatory network that offers novel insights into the molecular mechanisms governing immune regulation in LUAD. Future research should aim to translate these findings into clinical applications to enhance patient outcomes.

The purpose of the study is mainly to investigate anti proliferation of non-small cell lung cancer A549 cells and its mechanism by inhibition of CHK1 expression combined with gemcitabine. The mRNA and protein levels of genes were analyzed by RT-qPCR and Western blot, respectively. Cell viability was detected by CCK-8 assay and clone formation assay. The detection of the cell cycle was used by Annexin V/7-amino-actinomycin D apoptosis detection kit. Analysis of DNA damage was done by immunofluorescence and alkaline comet assay. The results showed that inhibition of CHK1 and gemcitabine combination significantly reduced the proliferation ability of the two cell lines. We also revealed the degradation of full-length PARP and reduced Bcl-2/Bax ratio on increased apoptosis. Inhibition of CHK1 expression leads to DNA damage, induces phosphorylation of γ-H2AX, and affects the repair of homologous recombination ability through Rad51. Mechanistically, gemcitabine increased phosphorylation-ATR and phosphorylation-CHK1, indicating activation of the DNA repair system and ATR-CHK1-CDC25A pathway. Inhibition of CHK1 resulted in increased synthesis of CDK2/Cyclin A2 and CDK2/Cyclin E1 complexes, and more cells entered the subsequent cell cycle, leading to S phase arrest and mitotic catastrophe. We identified inhibition of CHK1 as a potential treatment for NSCLC and confirmed that inhibition of this kinase could overcome acquired gemcitabine resistance.

Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CINhigh cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

The heterogeneity of cancer-associated fibroblasts (CAFs) has become a crucial focus in understanding cancer biology and treatment response, revealing distinct subpopulations with specific roles in tumor pathobiology. CAFs have also been shown to promote resistance in lung cancer cells to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the specific CAF subsets responsible for driving tumor advancement and resistance to EGFR-TKIs in lung adenocarcinoma (LUAD) remain poorly understood.

We integrate multiple scRNA-seq datasets to identify cell subclusters most relevant to tumor stage, patient survival, and EGFR-TKIs response. Additionally, in vitro and in vivo experiments, clinical tissue sample immunohistochemistry and patient plasma ELISA experiments are performed to validate key findings in independent LUAD cohorts.

By analyzing multiple scRNA-seq and spatial transcriptomic datasets, we identified a unique subset of CXCL14+ myofibroblastic CAFs (myCAFs), emerging during the early differentiation phase of pan-cancer invasiveness-associated THBS2⁺ POSTN⁺ COL11A1⁺ myCAFs. Notably, plasma levels of CXCL14 in LUAD patients correlate significantly with tumor stage. Mechanistically, this subset enhances tumor aggressiveness through epithelial-to-mesenchymal transition and angiogenesis. Among standard treatment regimens, transitional CXCL14+ myCAFs specifically confer resistance to EGFR-TKIs, while showing no significant impact on chemotherapy or immunotherapy outcomes. Through a pharmacological screen of FDA-approved drugs, we identified Filgotinib as an effective agent to counteract the EGFR-TKIs resistance conferred by this CAF subset.

In summary, our study highlights the role of the differentiated stage from transitional CXCL14+ myCAFs to invasiveness-associated myCAFs in driving tumor progression and therapy resistance in LUAD, positioning Filgotinib as a promising targeted therapy for this process. These insights may enhance patient stratification and inform precision treatment strategies in LUAD.

Single-cell analysis identifies transitional CXCL14+ myofibroblastic cancer-associated fibroblasts (myCAFs) predominantly exist in the advanced-stage lung adenocarcinoma (LUAD). Transitional CXCL14+ myCAFs fuel metastasis by promoting epithelial-mesenchymal transition (EMT) and angiogenesis on the spatial level. CXCL14 is a potential diagnostic marker for LUAD patients and predict the occurrence of metastasis. Transitional CXCL14+ myCAFs induce the resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and JAK1 inhibitor, filgotinib could reverse the effect.

Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. Agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed-forward loop linking agrin-EGFR rigidity response to YAP-TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR-YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin-EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR-addicted lung cancers.

Nanotechnology has revolutionized cancer therapy by enabling targeted drug delivery and overcoming limitations associated with conventional chemotherapy. In this study, we explored the anticancer potential of gold-iron oxide (Au-Fe3O4@PEG) nanourchins (NUs), a class of nanoparticles with unique shape, surface features, and plasmonic properties. We tested NUs on several cancer cell lines, including A375 (melanoma), MCF7 (breast), A549 (lung), and MIA PaCa-2 (pancreatic), and observed significant dose-dependent cytotoxicity, with A549 cells exhibiting the highest resistance. Our findings also demonstrate that NUs induce oxidative stress, disrupt mitochondrial function, and activate autophagic and paraptotic cell death pathways in A549 lung cancer cells. Additionally, we explored the potential of NUs to enhance the efficacy of platinum-based chemotherapy, specifically cisplatin, in A549. The results provide valuable insights into the therapeutic potential of NUs in the context of cancer treatment, particularly for overcoming drug resistance and enhancing the effectiveness of conventional chemotherapy.

Oncogenic RAS mutations are among the most common in human cancers. To target the active, GTP-bound state of RAS(ON) directly, we employed an innovative tri-complex inhibitor (TCI) modality. Formation of a complex with an intracellular chaperone protein CypA, an inhibitor, and a target protein RAS blocks effector binding, inhibiting downstream RAS signaling and tumor cell proliferation. Herein, we describe the structure-guided SAR journey that led to the discovery of daraxonrasib (RMC-6236), a noncovalent, potent tri-complex inhibitor of multiple RAS mutant and wild-type (WT) variants. This orally bioavailable bRo5 macrocyclic molecule occupies a unique composite binding pocket comprising CypA and SWI/SWII regions of RAS(ON). To achieve broad-spectrum RAS isoform activity, we deployed an SAR campaign that focused on interactions with residues conserved between mutants and WT RAS isoforms. Concurrent optimization of potency and drug-like properties led to the discovery of daraxonrasib (RMC-6236), currently in clinical evaluation in RAS mutant advanced solid tumors (NCT05379985; NCT06040541; NCT06162221; NCT06445062; NCT06128551).

Lung cancer remains one of the most widespread and deadliest malignant tumors globally, with a particularly high mortality rate among all cancers. Recently, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a crucial treatment strategy for lung cancer patients, following surgical intervention, radiotherapy, chemotherapy, and targeted drug therapies. However, the therapeutic limitations are caused owing to their low response rate and undesirable side effects such as immune-related pneumonitis. Therefore, developing new strategies to improve the efficacy of ICIs while minimizing immune-related adverse events will be crucial for cancer immunotherapy. The tumor immune microenvironment plays a significant role in the success of lung cancer immunotherapy, and the immunosuppressive characteristics of the immune microenvironment are one of the major obstacles to the poor immunotherapeutic effect. Phytochemicals, naturally occurring compounds in plants, have shown promise in enhancing cancer immunotherapy by remodeling the immunosuppressive microenvironment, offering the potential to increase the efficacy of ICIs. Therefore, this review summarizes the associated mechanisms of phytochemicals remodeling the immunosuppressive microenvironment in lung cancer. Additionally, the review will focus on the synergistic effects of combining phytochemicals with ICIs, aiming to improve anticancer efficacy and reduce side effects, which may hopefully offer novel strategies to overcome current limitations in immunotherapy.

To develop and validate a fluorine-18-fludeoxyglucose (18F-FDG) PET/CT-based radiomics nomogram for preoperative prediction of the International Association for the Study of Lung Cancer (IASLC) grading and recurrence-free survival (RFS) in patients with clinical stage I pure-solid invasive lung adenocarcinoma (LADC). MATERIALS AND METHODS: 418 patients with clinical stage I pure-solid invasive LADC who underwent preoperative 18F-FDG PET/CT examination were retrospectively enrolled. All patients were separated into the low-grade group (grade I and II; n=315) and the high-grade group (grade III; n=103) according to the IASLC grading system, and the cohort was randomly divided into a training set (n=292) and a testing set (n=126) at a ratio of 7:3. Radiomics features were extracted from CT and PET images in regions of the entire tumor. Multivariate analysis identified the independent predictors for IASLC grading and RFS. The Radscore, along with clinical and radiological features were combined to establish a predictive nomogram.

The ultimate Radiomics model, achieving AUCs of 0.838 and 0.768 in the training and testing sets. The multivariate logistic regression showed that higher maximum standard uptake value (SUVmax), cavity presence are the independent risk factors for IASLC grading. The integrated nomogram showed superior prediction performance than CT model (p=0.001) and PET model (p=0.028) in the training set. Furthermore, both pathological grade and preoperatively predictive IASLC grade derived by nomogram significantly stratified patients for RFS, with 5-year survival rates showing marked differences between low-grade and high-grade LADC (p<0.001).

The preoperative PET/CT-based radiomics nomogram represents a potential biomarker for predicting IASLC grade and RFS in patients with clinical stage I pure-solid invasive LADC.

Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet the heterogeneous underlying therapeutic outcomes remain underexplored. We applied single-cell RNA and TCR sequencing (scRNA/TCR-seq) to analyze surgical tumor samples from 234 NSCLC patients post-neoadjuvant chemo-immunotherapy. Analyses revealed five distinct TIME subtypes with varying major pathological response (MPR) rates. MPR patients had elevated levels of FGFBP2+ NK/NK-like T cells, memory B cells, or effector T cells, while non-MPR patients showed higher CCR8+ Tregs. T cell clonal expansion analyses unveiled heterogeneity in non-MPR patients, marked by varying expansions of Tex-relevant cells and CCR8+ Tregs. Precursor exhausted T cells (Texp cells) correlated with recurrence-free survival, identifying a patient subgroup with reduced recurrence risk despite lack of MPR. Our study dissects TIME heterogeneity in response to chemoimmunotherapy, offering insights for NSCLC management.

Epigenetic changes, such as LSD1 dysregulation, contribute to acquired resistance in EGFR mutant NSCLCs and reduce the effectiveness of current therapeutics. To address the challenges, we herein reported the structure-based design of new LSD1/EGFR dual inhibitors, of which ZJY-54 represents the shortlisted lead compound with high potency, selectivity, and unique dual modes of action (namely irreversibly binding to EGFR but reversibly binding to LSD1). ZJY-54 effectively inhibited growth in both parent- and TKI-resistant NSCLC cells. In H1975 cells, ZJY-54 induced accumulation of H3K4me2 and H3K9me2, as well as inhibited phosphorylation of EGFR signaling. ZJY-54 showed favorable PK profiles and effectively inhibited tumor growth in the H1975 xenograft model. ZJY-54 represents the best-in-class LSD1/EGFR dual inhibitor and warrants further preclinical development for treating NSCLCs. These findings highlight the therapeutic potential of LSD1/EGFR dual inhibitors in drug-resistant cancers where EGFR and LSD1 were dysregulated.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.