Translational lung cancer research最新文献

Background: For advanced non-small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) expression <1% and no actionable oncogenic alterations, pembrolizumab plus chemotherapy (Pembro-chemo) is widely regarded as the current standard of care. However, emerging therapeutic combinations and preliminary results from ongoing trials challenge its superiority, particularly across different histologic types. Therefore, this study aimed to appraise the effectiveness and safety of first-line treatment for PD-L1 <1% advanced, non-squamous and squamous NSCLC.

Methods: PubMed, Ovid Medline, the Cochrane Library, and Embase were searched from database inception to August 15, 2025, to identify phase III randomized controlled trials (RCTs) that explored first-line treatments in treatment-naïve advanced NSCLC, PD-L1 <1%, no epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations; and reported any efficacy outcome were eligible for inclusion. Treatment effectiveness was quantified using overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Surface under the cumulative ranking value (SUCRA) was used to rank the therapies. Risk of bias for included RCTs was assessed using the Cochrane Risk of Bias 2 tool.

Results: Twenty-five phase III RCTs involving 5,815 participants were eligible. Overall, 21 first-line treatments were identified. In terms of OS, pembrolizumab + chemotherapy + canakinumab (Pembro-chemo-canakinumab) (SUCRA =0.90) showed great potential in improving outcomes, although its long-term efficacy still needed to be validated. Nivolumab + ipilimumab (Nivo-ipi) (SUCRA =0.78) closely followed. Both top regimens showed non-significant superiority over Pembro-chemo. Regarding PFS, nivolumab + chemotherapy + bevacizumab (SUCRA =0.88), and serplulimab + chemotherapy (SUCRA =0.87) were the optimal regimens. Specifically for non-squamous patients, Pembro-chemo was optimal for OS (SUCRA =0.90), followed by Nivolumab + chemotherapy + bevacizumab (SUCRA =0.82). Nivolumab + chemotherapy + bevacizumab optimized PFS, with an hazard ratio (HR) of 0.52 [95% confidence interval (CI): 0.30-0.92 vs. Pembro-chemo]. For squamous patients, nivolumab + ipilimumab ± chemotherapy (Nivo-ipi-chemo) led in OS, while serplulimab + chemotherapy in PFS.

Conclusions: First-line personalized treatment for PD-L1 <1%, advanced NSCLC should be histology-based, balancing efficacy and toxicity. Pembro-chemo and nivolumab + chemotherapy + bevacizumab combinations are recommended as the optimal first-line options for non-squamous patients, and Nivo-ipi-chemo for squamous patients.

Background: The correlation between programmed death-ligand 1 (PD-L1) expression and the efficacy of first-line chemoimmunotherapy in advanced KRAS-mutant non-small cell lung cancer (NSCLC) is inconsistent across studies, possibly due to the spatial heterogeneity of PD-L1 expression. We characterized the PD-L1 expression profile at different tumor sites and its impact on the clinical efficacy of first-line immunochemotherapy in advanced KRAS-mutant NSCLC patients.

Methods: A retrospective analysis was performed on 302 patients with advanced KRAS-mutant NSCLC who received first-line immunochemotherapy from January 2018 to December 2022. Patients were categorized by biopsy sites: primary lung lesions (n=211) and metastatic lymph nodes (n=91). PD-L1 expression was stratified into <1%, 1-49%, and ≥50%. Primary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).

Results: Median PFS was 9.07 months overall, 7.27 months for PD-L1 <1%, 8.30 months for PD-L1 =1-49%, and 15.00 months for PD-L1 ≥50% (P<0.001). The corresponding median PFS values for patients with primary lung lesions were 7.23, 8.30, and 15.03 months, which were statistically significant (P=0.001). In contrast, no significant differences in PFS were observed among the PD-L1 subgroups for patients with metastatic lymph nodes (P=0.17). Moreover, the non-G12C subgroup exhibited a more pronounced PD-L1 expression heterogeneity between the primary and metastatic sites than the G12C subgroup.

Conclusions: In advanced KRAS-mutant NSCLC, the PD-L1 expression in primary lung lesions may predict first-line immunochemotherapy efficacy, while PD-L1 expression in metastatic lymph nodes lacks predictive value, especially in non-G12C mutations.

Background: Tumor invasion is a critical step in tumorigenesis and represents an important therapeutic target. However, the molecular mechanisms underlying the invasion process of lung adenocarcinoma (LUAD) remain poorly understood. In this study, we investigated the transcriptomic and epigenetic alterations occurring during LUAD invasion to elucidate the key biological processes.

Methods: Frozen section of LUAD tumors, which contained both invasive and non-invasive subtypes, was selected as the study model. These subtypes were identified, micro-dissected, and separately processed for RNA sequencing (RNA-seq). Subsequent analysis identified differentially expressed genes (DEGs) and significantly enriched biological processes. Additionally, RNA-seq data from independent LUAD tissues were analyzed to screen for critical genes, and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was conducted to explore potential regulatory mechanisms. Finally, survival analysis was performed using The Cancer Genome Atlas (TCGA) database to validate the clinical relevance of the identified genes.

Results: Subtype-specific RNA-seq analysis revealed that alteration in the extracellular matrix (ECM) was a key hallmark of LUAD invasion, which was validated by transcriptomic changes in independent tissue samples. Furthermore, several of these ECM genes were significantly associated with LUAD prognosis. Based on these findings, we hypothesized that epigenetic alterations during LUAD progression may drive these ECM changes, and that subsequent remodeling of the immune microenvironment may also contribute to the invasive process.

Conclusions: Our integrated analysis demonstrated that epigenetic and transcriptomic dysregulation-induced ECM alterations were critical for LUAD invasion. Specifically, key ECM genes, including AGER and CGNL1, were identified as central regulators of invasion and thus represent promising therapeutic targets for LUAD.

Background: Altered expression of microRNAs (miRNAs) is implicated in lung carcinogenesis, but little research has investigated the association of miRNA alterations with lung cancer stage or smoking status. To identify such alterations in lung adenocarcinoma, we conducted miRNA profiling.

Methods: Lung adenocarcinoma specimens and paired nonneoplastic lung tissues from 58 patients who had received no preoperative therapy and underwent tumor resection from 1991 to 2006 were collected from tumor tissue banks. Thirty (52%) of the tumors were stage I and 28 (48%) stage II or higher. Twenty-five (43%) patients were nonsmokers and 33 (57%) were smokers. To identify miRNAs of which its expression was associated with disease stage and/or smoking status, we performed subgroup analyses based on disease stage and smoking status, alongside overall profiling of all samples. miRNA expression was profiled using a microarray kit in tumors and paired nonneoplastic lung tissues. We assessed the fold changes (FCs) and local false discovery rates (FDRs) for the intercept in addition to P values.

Results: Of the 706 miRNAs examined, 64 had overall altered expression. Of these, 36 (56%) were associated with all stages of adenocarcinoma in both smokers and nonsmokers. In stage-based analysis, 20 altered miRNAs were associated with stage I disease and 38 with stage II or higher disease. Of the 20 miRNAs associated with stage I adenocarcinoma, 4 were miR-200 family members, and miR-200b was the most highly upregulated. Analysis based on smoking status identified 38 altered miRNAs in nonsmokers and 6 altered miRNAs in smokers. Three miR-200 family members were significantly altered in nonsmokers. Among the miRNA alterations associated with stage I adenocarcinoma in nonsmokers, we found alterations in all 5 miR-200 family members (miR-200b, miR-200a, miR-141, miR-429, and miR-200c).

Conclusions: Our identification of miRNA alterations associated with early-stage lung adenocarcinoma in nonsmokers, especially alterations in the miR-200 family, suggests that these miRNAs may play a unique role in the early stages of lung carcinogenesis and progression in nonsmokers and that they may be useful as markers for the early detection of lung cancer.

Background and objective: The incidence of multi-focal lung cancers (MFLCs) has increased with the widespread use of low-dose computed tomography, posing significant diagnostic and therapeutic challenges, particularly in differentiating multiple primary lung cancers from intrapulmonary metastasis. Surgical resection remains the standard treatment for early localized disease; however, it is often unsuitable for patients with multi-focal tumors, lesions near vital structures, or impaired lung function. This review aims to summarize current evidence on the use of minimally invasive bronchoscopic platforms, including robotic-assisted bronchoscopy (RAB) and electromagnetic navigation bronchoscopy (ENB), in the diagnosis and treatment of MFLCs.

Methods: A literature search of PubMed, Embase, and Web of Science was performed with a primary search on February 28, 2025 and a final update on September 30, 2025; only English-language publications were included. Keywords included "multi-focal lung cancer", "robotic-assisted bronchoscopy", "electromagnetic navigation bronchoscopy", "bronchoscopic ablation", and related terms. Relevant original studies, clinical trials, case series, reviews, and abstracts were included.

Key content and findings: RAB and ENB enable precise localization and access to peripheral lung lesions, enabling diagnostic biopsy and bronchoscopic ablation while preserving lung tissue. These approaches are particularly advantageous for patients who are poor surgical candidates, allowing the treatment of multiple lesions in a single session with shorter recovery times. Integration with stereotactic body radiation therapy, immunotherapy, and molecular profiling may further enhance local control and personalize therapy.

Conclusions: Bronchoscopic navigation platforms represent a promising addition to multidisciplinary MFLCs management by broadening eligibility for minimally invasive treatment and preserving lung function. With continued refinement and incorporation into multimodal strategies, these technologies may reshape therapeutic algorithms and influence future clinical practice and research direction.

Background: Small cell lung cancer (SCLC) represents an aggressive malignancy characterized by marked heterogeneity and neuroendocrine differentiation. Despite its clinical significance, the functional landscape of neuroendocrine function, while neuroactive-signaling-related genes (NRGs) in SCLC pathogenesis remains poorly characterized. Therefore, the aim of this study is to classify SCLC based on neuroactive signaling networks and to analyze the characteristics of these classifications in relation to the immune microenvironment.

Methods: Through integrated analysis of bulk transcriptomic profiling from 79 primary SCLC tumors and single-cell transcriptomic profiling from 11 SCLC tumors, we employed a consensus clustering algorithm to deconvolute transcriptional programs underlying neuroactive signaling networks. Molecular functions and tumor-infiltrated immune cells were estimated from bulk transcriptomes using bioinformatics methods. Single-cell transcriptomic analysis was implemented for cross-validation and cellular characterization.

Results: Bulk-seq analyses reported that the transcriptional variability of three major clusters of tumors were associated with different clinical outcomes and biological pathways. Clinical, genomic, and immunological characteristics were observed among three clusters. Furthermore, the key genes module of cluster with the worst survival were identified as neuroactive-signaling-related signature (NRS) and used to classify tumor samples into two distinct intra-tumoral subtypes (H-NRS and L-NRS) with single-cell transcriptomic data. At single-cell level, malignant cells in H-NRS tumor were in later cell state and had more frequent cellular communication. And NRS subsequently was identified as a biomarker correlated with better prognosis for patients receiving chemoimmunotherapy. It was found that Natriuretic Peptide C (NPPC), as one of the key genes in NRS, was overexpressed in SCLC tumor cells and correlated with poor prognosis. Treatment with C-type natriuretic peptide (CNP) facilitates cellular migration and metastatic potential.

Conclusions: This study proposes a novel molecular taxonomy for SCLC grounded in neuroactive signaling networks, suggests a potential prognostic biomarker to aid in therapeutic stratification, and identifies NPPC as a candidate therapeutic target worthy of further investigation in metastatic SCLC. Our findings may help bridge gaps in understanding between neuroendocrine biology and tumor microenvironment (TME) dynamics during SCLC evolution.

Background: Subcutaneous (SC) lung tumor models are widely used in preclinical studies due to their technical simplicity but fail to recapitulate the complex microenvironment, immune landscape, and metastatic behavior of human lung cancers. These limitations hinder the translational value of such models, particularly in evaluating immunotherapies and metastasis-related mechanisms. There is a critical need for more physiologically relevant in vivo models that better reflect clinical tumor characteristics and disease progression. To address these limitations, we sought to develop a reproducible orthotopic lung cancer (LuO) model that enables detailed study of tumor progression, immune infiltration, and metastatic dynamics.

Methods: We established and characterized a thoracotomy-based LuO model using a panel of human and murine lung cancer cell lines implanted into the pulmonary parenchyma of immunodeficient and syngeneic mice. Tumor progression was monitored longitudinally using bioluminescence imaging (BLI) and micro-computed tomography (CT). Comparative analyses with SC tumors were performed using immunohistochemistry, multiplexed immunofluorescence, transcriptomic and proteomic analyses. Circulating tumor cells (CTCs) and spontaneous metastases were isolated and functionally characterized.

Results: The orthotopic model reliably generated solitary intrapulmonary tumors that closely mimic human lung cancer in growth pattern, vascularization, and progression. Compared to SC tumors, orthotopic tumors exhibited significantly enhanced vascular density, reduced hypoxia and DNA damage, and increased proliferation. Immune profiling revealed enriched and spatially organized infiltrates of CD4⁺, CD8⁺ T cells, dendritic cells (DCs), and myeloid populations in orthotopic tumors, forming structures analogous to those found in patient tumors. Moreover, orthotopic tumors released CTCs capable of forming spontaneous and site-specific metastases to clinically relevant organs. Transcriptomic and proteomic profiling of metastasis-derived cell lines uncovered conserved pro-metastatic signatures and niche-specific adaptations.

Conclusions: This LuO model offers a reproducible, clinically relevant platform that captures important aspects of human lung cancer biology, including immune landscape, tumor microenvironment (TME), and metastatic progression. Its superior anatomical and immunological fidelity makes it a valuable preclinical tool for evaluating therapeutic strategies and dissecting molecular mechanisms of metastasis.

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide. Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) presents unique clinical challenges, including frequent central nervous system (CNS) metastases. At present, comparative real-world data on ALK inhibitors remain limited. This study aimed to compare real-world progression-free survival (PFS) and overall survival (OS) among patients with ALK-positive NSCLC treated with first-line alectinib or brigatinib using nationwide South Korean data.

Methods: This retrospective cohort study analyzed anonymized data from South Korea's Health Insurance Review and Assessment Service, covering January 2007 to December 2023. Patients diagnosed with ALK-positive NSCLC (ICD-10: C34x) and treated with either alectinib or brigatinib as first-line monotherapy were included. Patients with prior lung surgery or other malignancies were excluded. Baseline demographics and comorbidities were collected. The primary outcomes were PFS and OS, as measured from ALK inhibitor initiation.

Results: The final cohort included 1,009 patients with ALK-positive NSCLC. The mean age was 61.6 years, and 49.5% were male. Alectinib was associated with a significantly longer PFS. Brigatinib showed a higher OS in the unadjusted analysis; however, this difference was not statistically significant after multivariable adjustment. Transition to lorlatinib was associated with extended survival in both groups, reflecting its use as a later-line therapy following resistance.

Conclusions: In this real-world cohort of ALK-positive NSCLC patients, both alectinib and brigatinib were associated with extended survival, with alectinib showing longer PFS. Findings should be interpreted descriptively. Alectinib demonstrated superior disease control in terms of PFS. Further research is warranted to optimize treatment sequence strategies for ALK inhibitors.

Background: Recent evidence highlights the importance of lipid metabolic reprogramming in lung adenocarcinoma (LUAD) progression. Due to the limitations of conventional techniques, the fine structure of lipids cannot be identified. The metabolic changes of lipid structural features-particularly carbon-carbon double bond (C=C) positional isomers-remain underexplored. This study aims to characterize the structural alterations of lipids, especially C=C positional isomers, in LUAD tissues to elucidate their potential roles in tumor progression.

Methods: We performed deep structural lipidomic profiling on paired normal lung (N) and LUAD (T) tissue samples using a combination of photochemical reaction-based structural analysis (Ω Analyzer) and liquid chromatography-mass spectrometry (LC-MS). Lipid species were characterized at three structural levels: lipid class, molecular species, and C=C positional isomer. Relative quantitative analyses were conducted to identify differences in total composition, unsaturation levels, and the distribution of C=C isomers between N and T groups.

Results: A total of 794 phospholipid species were identified at the C=C isomer level, with the T group exhibiting a slightly higher overall number of identified lipids compared to the N group. Polyunsaturated lipids displayed notable upregulation in the T group and facilitated robust clustering between normal and cancer tissues. Furthermore, analyzing C=C positional isomers revealed significant differences in their relative abundances between the two groups: lipids enriched in C18:1(Δ9) were predominantly upregulated in T group samples, whereas those carrying C18:1(Δ8) were generally downregulated.

Conclusions: Our findings demonstrate that deep structural lipidomic analysis yields crucial insights into the lipid reprogramming of LUAD. In particular, the relative abundances of C=C positional isomers hold promise as novel diagnostic markers and therapeutic targets for LUAD.

Background: Time-to-surgery is used as a surrogate quality indicator within lung cancer care. However, its definition is not clearly defined in the literature. This study aimed to explore the evidence on optimal time-to-surgery interval with no negative impact on disease progression or oncological outcomes.

Methods: A systematic search was performed in January 2025 through MEDLINE, EMBASE, and Cochrane databases. Studies about lung cancer patients with treatment interval description until surgery were included.

Results: Eighty-six studies were included with a clear definition of the treatment interval until surgery. Starting points of the interval varied widely, of which pathological diagnosis was reported most often. Thirty-six studies also included associations of time-to-surgery with oncological outcomes. Overall, 47% of the included studies associated a delay in treatment interval with worse outcomes, 33% found no association, and in 19% the association differed per lung cancer stage or type of outcome. Inconsistency was seen in the definition of timely surgery, ranging from 21 to 90 days, influencing the reported outcome measures and comparability. Most studies chose the tipping point for delayed surgery at or beyond 6 weeks, and the most reported outcome was overall survival (OS). For OS, two thirds of the included study groups associated a delay in time-to-surgery with worse survival, with a very heterogeneous cut-off point between timely and delayed surgery.

Conclusions: Within lung cancer care, there is no clear definition of treatment interval until surgery, nor consensus on the definition of timely surgery. The relation between treatment interval and outcomes is inconsistent and requires more structured evidence. We suggest using pathological diagnosis as a starting point, and a 6-week timeframe as a basis to define timely surgery instead of "as soon as possible", without significantly compromising oncological safety. Defining an interval can reframe waiting time into structural preoperative preparation time, unlocking the opportunity to implement prehabilitation and optimize patient outcomes.