Search Results (4,492)

Blood-based biomarkers have emerged as promising, minimally invasive tools for the diagnosis, prognostic stratification, and treatment monitoring of non-small cell lung cancer (NSCLC), including markers of tumor burden, tumor dissemination, immune signaling, and post-transcriptional regulation. However, evidence across biomarker classes remains fragmented. This study aimed to synthesize published evidence on major blood-based biomarkers relevant to diagnosis, prognosis, treatment stratification, and monitoring in NSCLC. PubMed was searched for systematic reviews and meta-analyses of blood-based biomarkers in NSCLC. Of 356 screened records, 82 underwent full-text review, and 57 systematic reviews/meta-analyses were included. Biomarkers were grouped into four categories: circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cytokines/soluble immune proteins, and non-coding RNAs (ncRNAs). Reported pooled effect estimates were extracted by biomarker class and evidence domain, and the methodological quality of included reviews was assessed using AMSTAR 2. Evidence was unevenly distributed across biomarker classes and evidence domains. Circulating ncRNAs were mainly represented in diagnostic and prognostic evidence; selected diagnostic ncRNAs, including miR-145, miR-25, and circRNAs, showed reported AUCs ranging from 0.83 to 0.85. ctDNA was represented across diagnostic, prognostic, treatment-stratification, and dynamic monitoring evidence, with ctDNA positivity associated with poorer survival or recurrence outcomes and ctDNA clearance or decline associated with improved outcomes. CTC evidence was primarily prognostic, with CTC positivity associated with worse overall survival and disease-free survival. Soluble immune biomarker evidence was also primarily prognostic, with elevated soluble PD-L1 and IL-6 associated with adverse survival outcomes and limited exploratory monitoring evidence for exosomal PD-L1. Overall, the evidence suggested distinct but complementary roles across biomarker classes, although direct head-to-head comparisons were lacking. Blood-based biomarkers show potential to support diagnosis, prognosis, and longitudinal monitoring in NSCLC, but their reported utility differs by biomarker class and clinical context. In the available review-level evidence, ncRNAs were mainly represented in diagnostic and prognostic evidence, while ctDNA was represented across diagnostic, prognostic, treatment-stratification, and dynamic monitoring evidence. CTCs were mainly represented in prognostic evidence, and soluble immune biomarkers were primarily represented in prognostic evidence, with limited exploratory evidence for dynamic monitoring. Further assay standardization, prospective validation, and direct comparative studies are needed before these biomarkers can be routinely integrated into clinical practice. Full article

Leptomeningeal metastasis (LM) is a severe and increasingly recognized complication of advanced non-small-cell lung cancer (NSCLC), particularly in patients with actionable genomic alterations. Although LM has historically been associated with poor outcomes, molecularly targeted systemic therapies with improved central nervous system (CNS) activity are reshaping its therapeutic landscape. This review summarizes current concepts in the pathogenesis, diagnosis, and risk stratification of LM, focusing on systemic treatment strategies for NSCLC harboring actionable driver alterations. We highlight the rationale and emerging evidence for next-generation tyrosine kinase inhibitors targeting EGFR, ALK, and other oncogenic drivers, and discuss their role as the cornerstone of LM management. Intrathecal chemotherapy, immunotherapy, and radiotherapy are also reviewed within a risk-adapted treatment framework. An individualized approach integrating molecular profiling, neurological status, and disease distribution is essential to optimize outcomes. Prospective studies are needed to refine systemic treatment strategies and establish evidence-based algorithms for this high-risk population. Full article

Treatment of non-small cell lung cancer (NSCLC) has been transformed by immunotherapy and targeted therapies. We aimed to characterize clinical features, treatment patterns, and healthcare resource use in patients with early and locally advanced NSCLC before incorporation of these therapies. This retrospective observational study included adults diagnosed with stage I–III NSCLC at four Spanish hospitals between 2014 and 2018, with follow-up until 2021, using artificial intelligence to extract data from electronic health records. A total of 951 patients were included (34.7% stage I, 16.7% stage II, 48.6% stage III), with a median age of 66 years and 31.9% female. Surgery was performed in 78.5% of stage I, 74.8% of stage II, and 35.5% of stage III patients. Among surgical patients, 62.5% received adjuvant chemo- and/or radiotherapy, 20.8% neoadjuvant therapy, and 15.7% both; among non-surgical patients, chemoradiotherapy was the most common treatment (50.4%). Beyond hospitalization, outpatient visits were the most frequently used healthcare resource. These findings provide a historical benchmark of NSCLC care before introduction of immunotherapy and targeted therapies in these settings, highlighting treatment variability and the need for earlier diagnosis, structured treatment pathways, and multidisciplinary management. Full article

Background: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and are associated with substantial molecular and immunological heterogeneity. However, the clinicopathological associations and prognostic relevance of KRAS mutation subtypes and co-occurring genomic alterations in relation to PD-L1 expression and survival outcomes remain incompletely understood, particularly in the immunotherapy era. Methods: This retrospective single-center study included 93 KRAS-mutant NSCLC patients identified among 543 consecutively sequenced cases between March 2024 and March 2025. KRAS mutation subtypes, co-mutations involving TP53, STK11, and KEAP1, PD-L1 expression status, clinicopathological features, and survival outcomes were evaluated. Overall survival was assessed using Kaplan–Meier analysis and Cox proportional hazards regression models. Results: KRAS mutations were detected in 17.1% of NSCLC patients. G12C was the most frequent KRAS subtype (38.7%), followed by G12V (18.3%) and G12D (14.0%). Co-occurring mutations were identified in 73.1% of cases, most commonly involving TP53 (40.9%) and STK11 (33.3%). PD-L1 expression was negative in 48.4% of patients, low in 28.0%, and high in 23.7%. No significant association was identified between KRAS mutation subtype and PD-L1 expression (p = 0.663). STK11-mutated tumors demonstrated a trend toward lower PD-L1 expression levels compared with STK11 wild-type tumors. However, none of the molecular variables retained independent prognostic significance. Immunotherapy was associated with significantly prolonged overall survival (median OS: 24 vs. 7 months, p = 0.013) and remained independently associated with improved survival in multivariate analysis (HR: 0.376, 95% CI: 0.204–0.694, p = 0.002). Advanced-stage disease independently predicted worse survival outcomes (HR: 13.43, 95% CI: 1.81–99.79, p = 0.011). Conclusions: KRAS mutation subtypes and co-occurring genomic alterations demonstrated limited independent prognostic significance in this real-world NSCLC cohort. In contrast, immunotherapy was associated with improved overall survival in this retrospective cohort. These findings should be interpreted as observational and hypothesis-generating rather than evidence of predictive treatment benefit. Larger prospective studies integrating genomic and immune biomarkers are warranted. Full article

A 64-year-old Asian woman diagnosed with synchronous breast ductal carcinoma in situ (DCIS) and stage IV EGFR-mutated non-small cell carcinoma of the lung (NSCLC). A decision was made to defer management of the DCIS and initiate Osimertinib for lung cancer treatment, since this was a life-limiting diagnosis. At 9 months, restaging FDG-PET CT showed an interval response in the NSCLC and complete loss of FDG avidity at the biopsy-proven DCIS site. Breast MRI confirmed complete imaging resolution of the DCIS. The clinical resolution of breast DCIS during third-generation EGFR inhibitor therapy has not been previously reported in humans and highlights a potential role for the EGFR/HER2 (ERBB) pathway in pre-invasive breast cancer. Full article

Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes, most patients do not respond to treatment or fail to achieve durable responses. Histone deacetylase inhibitors (HDACi) have emerged as promising immunomodulatory agents, with the potential to sensitize tumors to ICIs. We investigated the immunomodulatory effects of entinostat, a class I HDACi, in combination with dual ICI (anti-PD-1 and anti-CTLA-4) as well as with T-cell receptor (TCR) engineered T cells in preclinical NSCLC models. Methods: We employed human NSCLC cell lines and the immunogenic KRASG12D/p53-mutant KPN1.1 murine NSCLC cell line. In vitro, we assessed entinostat-induced changes in MHC class I and PD-L1 expression. In addition, we evaluated the effects of entinostat on a KRASG12D-specific TCR. In vivo, therapeutic efficacy and immune modulation were assessed by transplanting KPN1.1 cells subcutaneously and orthotopically into immunocompetent mice, followed by treatment with dual ICI, with or without entinostat. Immune populations in the spleen and blood were subsequently analyzed. Results: In vitro, entinostat induced the upregulation of MHC-I and PD-L1 expression in both human and murine NSCLC cell lines. In addition, entinostat treatment significantly enhanced antigen-specific tumor recognition and killing by T cells engineered to express a KRASG12D-specific TCR. In vivo, the addition of entinostat to dual immune checkpoint inhibition showed an incremental trend toward improved tumor growth control. Notably, entinostat plus dual ICI enhanced systemic immune activation, increasing circulating and splenic T-cell populations and significantly expanding both antigen-specific and overall effector CD8⁺ T cells. Consistently, the ex vivo co-culture of splenocytes from KPN1.1-bearing mice with KPN1.1 tumor cells demonstrated enhanced CD8⁺ antigen-specific T-cell recognition. Conclusions: In human and murine NSCLC models, entinostat potentiates TCR- and ICI-mediated tumor recognition through tumor-intrinsic and systemic immune modulation. These effects were reflected by increased MHC-I expression, expansion of antigen-specific effector CD8⁺ T cells, and enhanced CD8⁺ T-cell tumor recognition. These findings support a further evaluation of entinostat as a strategy to improve immunotherapy efficacy in NSCLC. Full article

Background: Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide over the past decade. Single-cell sequencing loses spatial location information and potential cell–cell interactions, making it difficult to interpret molecular features or biological phenomena. Tertiary lymphoid structures (TLSs) inherently require such spatial immune cell distribution information. Although associations between TLS and response to immune checkpoint inhibitors (ICIs) or chemotherapy have been reported, the relationship between TLS and neoadjuvant therapy (ICI combined with chemotherapy) remains unclear. Methods: We performed spatial transcriptomics on NSCLC samples (including one lung squamous cell carcinoma (LUSC) and one lung adenocarcinoma (LUAD)). Multiplex immunohistochemistry (mIHC) was used to identify the TLS, while immunohistochemistry staining (IHC) was used to identify the TLS status and cell characteristics. We evaluated the associations between (mature) TLS density, area proportion and patients’ responses in 66 patients. Results: Heterogeneity of immune cells in NSCLC was found. Gene ontology analysis and cell score comparison identified TLS with activated B and T cells inside, while plasma cells and macrophages were mainly distributed outside TLS. Four genes from antigen-presenting machinery (TAP1, TAP2, B2M, TAPBP) were more highly expressed inside TLS than outside them. Also, TLS exhibited heterogeneity, with both mature and immature TLS. Mature TLS showed an average area of 62,387.43 μm², while the immature TLS showed 51,189.90 μm². The Spearman correlation coefficient of B-cell number and mTLS area showed r = 0.900. TLS density and mature TLS (mTLS) density in the tumor bed were 1.95 ± 0.95 TLS/10 mm² (mean ± SD, n = 34) and 1.13 ± 0.77 mTLS/10 mm², significantly higher than that in the non-responder group (1.18 ± 1.15 TLS/10 mm², 0.70 ± 0.90 mTLS/10 mm², mean ± SD, n = 32) separately. B cells belonging to TLS had a significantly higher density (71.32 ± 55.71 cells/mm², mean ± SD, n = 34) in the responder group than the non-responder group (61.33 ± 111.95 cells/mm², mean ± SD, n = 32) normalized to the tumor bed area. Conclusions: Spatial transcriptomics reveals immune cell heterogeneity and distribution patterns in the NSCLC tumor bed, with activated B and T cells localized inside and plasma cells/macrophages outside. Antigen-presenting machinery (APM)-related genes were highly expressed in TLS accompanied by a high expression of upstream and downstream genes of MHC class I. mTLS have a larger area by mainly containing more B cells. The responder group had a significantly higher (mature) TLS density and larger (mature) TLS area proportion compared with the non-responder group, suggesting their potential function in anti-tumor effect in neoadjuvant treatment. Full article

Drug repurposing represents a rational and resource-efficient strategy to expand the oncological armamentarium by leveraging the established pharmacology, clinical experience, and safety-monitoring frameworks of approved non-oncological agents. Clozapine (CZP), an atypical antipsychotic characterized by broad receptor pharmacology, complex biotransformation, and clinically relevant toxicological liabilities, has emerged as a candidate of interest following preclinical evidence of context-dependent anticancer activity across multiple tumor types. As such, CZP provides an informative case study at the interface between therapeutic drug action and xenobiotic behavior. This review provides a critical and integrated synthesis of the current evidence supporting the repurposing of CZP in oncology, with particular emphasis on the relationship between its molecular mechanisms, dose–exposure requirements, pharmacological complexity, and potential toxicity. Analysis of in vitro and in vivo studies across glioblastoma, non-small cell lung cancer, breast cancer, and melanoma brain metastasis models indicates that CZP can impair tumor cell proliferation and survival through a form of mechanistic plasticity. Rather than acting through a single conserved pathway, CZP appears to disrupt shared upstream processes related to pro-survival signaling, cellular stress tolerance, and metabolic homeostasis, while engaging tumor-specific downstream responses, including autophagic cell death, mitochondria-dependent apoptosis, oxidative stress, and coordinated modulation of survival and angiogenic pathways. Despite this mechanistic rationale, translation remains substantially constrained, most notably by the order of magnitude gap between anticancer-effective concentrations in vitro and clinically achievable plasma exposures, requiring careful distinction between potentially useful anticancer pharmacology and nonspecific xenobiotic-induced cellular stress and clinically unacceptable toxicity. Key limitations include the discrepancy between anticancer-effective concentrations observed in vitro and exposures achievable during standard psychiatric dosing, the limited understanding of how CZP metabolism and metabolite formation may influence efficacy and toxicity, the absence of integrated pharmacokinetic–pharmacodynamic and toxicokinetic modeling, and the lack of dedicated clinical trial evidence. To address these challenges, this review examines complementary translational strategies, including patient-derived organoids, co-culture systems, microphysiological platforms, pharmacokinetic and toxicological modeling, and computational digital twin frameworks. Together, these approaches may support a biologically informed and risk-aware evaluation of CZP, helping to identify responsive tumor contexts, anticipate exposure-related liabilities, and prioritize rational combination strategies. By integrating therapeutic potential with xenobiotic pharmacology and toxicology, this review positions CZP within the evolving landscape of precision oncology and evidence-driven drug repurposing. Full article

Marine medicinal algae represent a valuable reservoir of bioactive metabolites for anticancer drug discovery, yet the efficient identification of target-relevant compounds from chemically complex marine matrices remains challenging. In this study, an integrated cathepsin B-oriented strategy was developed to discover, prioritize, isolate, and validate antitumor metabolites from the brown alga Sargassum polycystum. Affinity ultrafiltration LC-MS was first applied to screen CTSB-binding constituents from the crude extract, followed by molecular docking, molecular dynamics simulation, and gray relational analysis for multidimensional candidate prioritization. Seven CTSB-binding metabolites were characterized, including chlorogenic acid, caffeic acid, cynarin, loliolide, taxifolin, senkyunolide H, and dihydroactinidiolide, with binding degrees of 73.99–85.61% at 2.5 U/mL CTSB. Molecular docking showed predicted binding affinities ranging from −6.3 to −9.4 kcal/mol, compared with −10.2 kcal/mol for the positive control CA-074Me. Integrated computational and biological evaluation identified caffeic acid, cynarin, and taxifolin as the top-ranked candidates. Preparative recovery was then achieved using counter-current chromatography combined with semi-preparative HPLC, and the isolated compounds were structurally identified by LC-MS/MS and NMR. Cellular assays in NCI-H1975 cells suggested that these metabolites reduced CTSB-associated enzymatic activity and intracellular CTSB-related fluorescence signals to different extents, with phenolic acid-type compounds exhibiting comparatively stronger effects. At the extract level, S. polycystum dose-dependently suppressed NCI-H1975 xenograft tumor growth, with inhibition rates of 48.78%, 36.58%, and 22.86% in the high-, middle-, and low-dose groups, respectively, without evident hepatorenal histopathological toxicity. This effect was associated with reduced CTSB, Ki-67, and Bcl-2 staining, increased Bax staining, enhanced apoptosis, and ultrastructural alterations in tumor tissues. Overall, this study provides a practical CTSB-oriented workflow for discovering antitumor metabolites from marine medicinal algae and supports further investigation of S. polycystum as a potential source of anti-NSCLC candidates. Full article

Background: This study aimed to investigate the prognostic value of peripheral blood inflammatory markers and nutritional indices for overall survival (OS) in young patients with advanced non-small cell lung cancer (NSCLC) at initial diagnosis. Additionally, we sought to develop a survival prediction model based on combined indicators. Methods: We retrospectively analyzed the clinicopathological characteristics, inflammatory markers, and nutritional indices of young patients with advanced NSCLC initially diagnosed at the Fourth Hospital of Hebei Medical University between January 2013 and March 2025. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for OS. Three prognostic models were constructed: a clinical–inflammation model, a clinical–nutrition model, and a clinical–inflammation–nutrition model. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), concordance index (C-index), and decision curve analysis (DCA), with TNM staging as the reference. Results: A total of 514 patients were included, with a median follow-up of 56.6 months and a median survival time of 27.2 months. Multivariate analysis identified sex, liver metastasis, gene mutation, targeted therapy, white blood cell count, and serum albumin level as independent prognostic factors for OS. Among the three models, the clinical–inflammation–nutrition model showed the best predictive performance, with 1-, 3-, and 5-year AUCs of 0.788, 0.756, and 0.704, respectively, and a C-index of 0.711 (95% CI: 0.696–0.726). DCA further demonstrated its clinical net benefit. Conclusions: Peripheral blood inflammatory markers and nutritional indices are closely associated with survival in young patients with advanced NSCLC. In this exploratory single-center study, a prognostic model integrating clinicopathological factors, inflammatory markers, and nutritional indices showed better apparent predictive performance than models based on single categories of variables or TNM staging, warranting further validation in independent cohorts. Full article

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide and is characterized by therapeutic resistance, metabolic plasticity, and immune evasion. Accumulating evidence indicates that metabolic reprogramming not only supports tumor growth but also creates exploitable vulnerabilities linked to regulated cell death. Traditional Chinese medicine (TCM)-derived small molecules have attracted increasing attention owing to their structural diversity, multitarget properties, and broad pharmacological activities. In this review, we summarize recent advances in TCM-derived compounds targeting metabolism-associated regulated cell death in NSCLC, with a primary focus on ferroptosis and a cautious discussion of emerging cuproptosis- and disulfidptosis-related mechanisms. Ferroptosis has been extensively investigated in this context, with natural compounds shown to induce cell death through coordinated regulation of cystine transport, glutathione metabolism, GPX4 activity, iron homeostasis, and lipid peroxidation. In parallel, emerging studies suggest that certain natural products may influence copper-dependent cell death pathways and metabolic states associated with disulfide stress. These processes are closely linked to distinct metabolic features of NSCLC, including lipid dependency, copper homeostasis, and glucose utilization. Finally, we discuss major challenges for clinical translation, including poor bioavailability, off-target toxicity, insufficient biomarker stratification, and limited high-quality evidence, and highlight emerging strategies such as nanodelivery systems, structural optimization, and targeted protein degradation approaches. Overall, TCM-derived small molecules represent a promising source of metabolism-targeted therapeutics and provide a foundation for further exploration of regulated cell death in NSCLC. Current evidence is strongest for ferroptosis induction, whereas cuproptosis- and disulfidptosis-related mechanisms remain emerging areas that require further experimental validation in NSCLC models. Full article

Background/Objectives: Anaplastic lymphoma kinase (ALK) fusion is a driver gene translocation detected in 3–5% of patients with non-small-cell lung cancer (NSCLC). Next-generation sequencing (NGS)-based tests are the standard of care for detecting actionable gene alterations; however, false negatives remain a concern. Immunohistochemical staining is another reliable, rapid, and low-cost method for detecting ALK fusions. Previous studies have reported high concordance with NGS, although further studies are needed to draw definitive conclusions. Methods: A retrospective analysis was conducted on consecutive patients with NSCLC who were tested using the Oncomine Dx Target Test (ODxTT), an amplicon-based DNA and RNA NGS test for NSCLC, and ALK-immunohistochemistry (IHC) at our institution between 8 August 2019 and 11 April 2025. Results: Of 919 eligible patients included in this study, ALK fusion was detected in 30 (3.26%) patients, whereas ALK-IHC was positive in 35 (3.80%) patients. The concordance and κ coefficient of the two tests were 99.4% and 0.920, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of ALK-IHC for ODxTT were 100%, 99.4%, 85.7%, and 100%, respectively. Five discordant patients were NGS negative and IHC positive. Among the five discordant cases, one had a false-negative NGS result, whereas the remaining four had false-positive ALK-IHC results, including three patients with neuroendocrine carcinomas. Conclusions: ALK-IHC shows diagnostic accuracy comparable to ODxTT, although prudent interpretation is needed for patients without adenocarcinoma. Our findings suggest the complementary role of ALK-IHC alongside NGS-based testing, particularly in patients with a high pre-test probability of harbouring ALK fusions. Full article

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) representing the most common subtype. Despite major advances in immunotherapy, only a subset of patients benefits from current treatments, highlighting the need to better understand the tumor immune microenvironment (TIME) and the mechanisms underlying immune escape. In this context, extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in lung cancer. This review summarizes the current knowledge on the role of EVs in NSCLC progression and immune regulation. We discuss how EVs contribute to primary tumor growth, dissemination, and pre-metastatic niche formation through the transfer of proteins, metabolites and nucleic acids. Particular attention is given to EV-mediated modulation of immune cells, highlighting their role in both immune suppression and immune activation. Furthermore, we provide an overview of the emerging therapeutic applications of EVs in lung cancer, including their use as drug-delivery systems and immunotherapeutic platforms. Full article

Squamous cell lung cancer (SqCLC) accounts for 20–30% of non-small cell lung cancer (NSCLC) and remains associated with a poorer prognosis compared with adenocarcinoma. Despite advances in treatment, 5-year overall survival for advanced (stage IV) disease remains below 10–15%. Unlike non-squamous NSCLC, SqCLC is characterized by a high tumor mutational burden and complex genomic landscape dominated by alterations in tumor suppressor genes and lineage survival pathways including TP53, CDKN2A, PIK3CA, FGFR1, SOX2, and the NFE2L2/KEAP1 oxidative stress pathway, as well as dysregulation of the NOTCH signaling pathway, but it harbors relatively few actionable oncogenic drivers, resulting in limited treatments for targeted therapy. HER2 alterations can occur by multiple mechanisms, including activating mutations, gene amplifications, and protein overexpression. They comprise a very small percentage of NSCLC, with HER2 mutations reported in approximately 1–3% and HER2 amplifications observed roughly in 2–4%. While HER2 alterations are well characterized in lung adenocarcinoma, the prevalence, genomic context, and clinical significance of HER2 alterations in SqCLC remain incompletely defined. Advances in next-generation sequencing have led to improved ability to detect HER2 alterations and facilitated the development of HER2 targeted therapies. Available treatments for advanced/metastatic SqCLC have been historically limited to platinum-doublet chemotherapy, with immune checkpoint inhibitors such as anti-PD-1/PD-L1 newly emerging in the past decade. Selective HER2 tyrosine kinase inhibitors and HER2 antibody/drug conjugates have shown improved efficacy in HER2-altered NSCLC as shown in DESTINY-LUNG02 and BEAMION LUNG-1 trials; however, most of the enrolled patients had non-squamous histology, with minimal or no SqCLC-specific efficacy data reported. Future progress in HER2-altered SqCLC will require inclusion of SqCLC in HER2 basket trials, incorporation of comprehensive molecular profiling and standardized HER2 testing in squamous histology. This review summarizes the current state of knowledge of HER2 biology in SqCLC and highlights areas for future directions for precision oncology in SqCLC. Full article

MET pathway alterations have evolved from a niche translational interest into one of the most clinically actionable axes in non-small cell lung cancer (NSCLC). Three biologically distinct lesions—MET exon 14 (METex14) skipping mutations, focal high-level MET amplification, and c-Met protein overexpression—are now individually targetable, each with its own diagnostic prerequisites and therapeutic class. Selective type Ib MET tyrosine kinase inhibitors (capmatinib, tepotinib) anchor first-line therapy for METex14, while next-generation agents and type II inhibitors are being developed to address on-target D1228 and Y1230 resistance mutations. In parallel, MET amplification has emerged as a leading mechanism of acquired resistance to osimertinib in EGFR-mutated NSCLC, with the SAVANNAH, SACHI, and INSIGHT 2 trials providing biomarker-guided combination strategies. The 2025 accelerated approval of telisotuzumab vedotin for c-Met-overexpressing tumors expanded the therapeutic armamentarium beyond kinase inhibition. Despite these advances, lineage plasticity, polyclonal bypass signaling, and inconsistent diagnostic thresholds for MET amplification continue to limit durable benefit. This review integrates the molecular biology, current clinical evidence, resistance mechanisms, and a proposed 2025 treatment algorithm for MET-altered NSCLC, with emphasis on the translational interface between mutation class, drug class, and emerging combinatorial approaches. As a narrative review, it synthesizes peer-reviewed literature and pivotal trial and regulatory data through early 2026, identified by structured searches of PubMed and major oncology congress proceedings, and prioritizes sources that link mutation class to drug class and resistance mechanism. Full article