Search Results (4,603)

Lung cancer is currently the most frequently diagnosed malignancy worldwide, accounting for approximately 12.4% of all cancers and, despite major advances in molecularly targeted therapies and immunotherapy, represents the leading cause of cancer-related mortality, In recent years, antibody–drug conjugates (ADCs) have emerged as a novel therapeutic strategy, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of highly active payloads to selectively target tumor cells while limiting systemic toxicity. This narrative review summarizes the current role of ADCs in lung cancer, with particular focus on their structural components, mechanisms of action, and the biological features that determine treatment efficacy. We discuss the rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation. The principal mechanisms of primary and acquired resistance are also reviewed, including antigen modulation, altered intracellular trafficking, lysosomal dysfunction, drug efflux, tumor microenvironment-mediated immune suppression, and intratumor heterogeneity. In addition, we provide an overview of the safety profile of ADCs, highlighting the most clinically relevant adverse events and their underlying biological mechanisms. We also examine the evolving landscape of predictive biomarkers beyond antigen expression, including genomic, transcriptomic, proteomic, and liquid biopsy-based approaches, together with emerging spatial and single-cell technologies that may improve patient selection. Finally, we discuss future directions in the field, including novel payloads, next-generation linker technologies, bispecific ADCs, combination strategies, and personalized ADC development. Overall, ADCs are rapidly reshaping the therapeutic landscape of lung cancer. Continued optimization of drug design, biomarker-driven patient selection, and a deeper understanding of resistance mechanisms will be essential to fully realize their clinical potential. Full article

Background/Objectives: ALK tyrosine kinase inhibitors (TKIs) have improved outcomes in patients with metastatic ALK-rearranged non-small cell lung cancer (NSCLC). However, real-world data on long-term outcomes, prognostic factors, and treatment sequencing remain limited. This study aimed to evaluate treatment outcomes, prognostic factors, and lorlatinib efficacy in different treatment settings. Methods: We retrospectively analyzed 83 patients with metastatic ALK-rearranged NSCLC treated with ALK TKIs at a tertiary oncology center. Survival outcomes, prognostic factors, treatment sequences, and adverse events were analyzed using Kaplan–Meier and Cox regression methods. Results: The median follow-up duration was 69.4 months, and the median overall survival (OS) was 73.9 months (95% CI, 58.51–89.32). Median OS was 84.8 months with first-line alectinib and 63.6 months with crizotinib. Median progression-free survival (PFS) durations were 47.5, 23.0, and 14.9 months for alectinib, brigatinib, and crizotinib, respectively. ECOG performance status, histological subtype (adenocarcinoma vs. non-adenocarcinoma), and PD-L1 expression were significant prognostic factors. First-line lorlatinib demonstrated durable disease control, with median PFS not reached and a 24-month PFS rate of 80%. Later-line lorlatinib showed continued activity, with median PFS-2 and PFS-3 of 12.2 and 6.1 months, respectively. Treatment-related adverse events were generally manageable. Conclusions: This real-world study provides long-term outcomes and prognostic insights in metastatic ALK-rearranged NSCLC. ECOG performance status, histological subtype, and PD-L1 expression were independent prognostic factors for OS. First-line lorlatinib findings suggest durable disease control but remain preliminary and require confirmation with longer follow-up. Full article

Background: Although high PD-L1 expression correlates with improved outcomes to immune checkpoint inhibitor (ICI), it remains an imperfect predictive biomarker. DNA damage response (DDR) pathway alterations are closely associated with antitumor immunity, shaping tumor immunogenicity and the immune microenvironment. This study evaluates the distribution and clinical impact of DDR alterations in advanced Non-small cell lung cancer (NSCLC) with Programmed death-ligand 1 (PD-L1) ≥ 50%, providing insights for personalized treatment selection and response prediction. Experimental Design: Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received first-line ICI-based therapy were retrospectively enrolled. Tumor tissue samples underwent targeted next-generation sequencing using a comprehensive cancer panel, with a predefined 35-gene DDR panel used to identify and classify pathogenic or likely pathogenic DDR alterations. The associations between genomic DDR alteration status, clinicopathologic characteristics, cytokine profiles, and immunotherapy outcomes were evaluated. Results: Among 121 patients, 72 (59.5%) were classified as DDR-positive and 49 (40.5%) as DDR-negative based on genomic DDR alterations. DDR-positive patients exhibited a higher burden of DDR alterations and TMB, and DDR-positive status remained independently associated with improved outcomes after adjustment for clinical factors and TMB. DDR-positive patients had higher DCB rates and IL-2 levels, whereas TNF-α and IL-6 levels were elevated in DDR-negative patients. DDR-positive status was associated with longer PFS than DDR-negative status (median, 12.7 vs. 8.9 months), with the benefit of chemo-immunotherapy mainly observed in DDR-positive patients. Conclusions: Genomic DDR alterations are associated with distinct immune profiles and may represent a potential biomarker for immunotherapy stratification. DDR-positive patients may derive greater benefit from chemo-immunotherapy, supporting further prospective investigation. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, highlighting the urgent need for novel therapeutic strategies. This study aimed to identify bioactive small RNAs derived from Maytenus hookeri Loes. and evaluate their anti-tumor potential against non-small cell lung cancer (NSCLC). The 50 most abundant small RNAs were synthesized and screened in NCI-H460 cells using the MTS assay. Among them, MDM-sRNA-39 significantly inhibited cell viability and was selected for further evaluation of its anti-tumor activity. It reduced the percentage of cells that traversed the Transwell membrane and promoted apoptosis in NCI-H460 cells. Bioinformatics prediction suggested KRAS as a potential target of MDM-sRNA-39, and KRAS was among the targets experimentally validated by dual-luciferase reporter assays, RT-qPCR, and Western blot, showing that MDM-sRNA-39 suppresses KRAS expression at both mRNA and protein levels. In vivo, MDM-sRNA-39 was orally administered as a bencaosome in a Kras^LSL-G12D/p53^LoxP/LoxP autochthonous lung cancer mouse model. Tumor burden was reduced and cleaved caspase-3 staining was increased in the mouse model. Collectively, these findings identify MDM-sRNA-39, a synthetic small RNA based on a sequence identified from Maytenus hookeri Loes., as a candidate with anti-tumor activity, supporting the potential strategy for developing RNA-based therapeutics from traditional Chinese medicine. Full article

Background: The integration of immune checkpoint inhibitors (ICIs) has transformed metastatic non-small cell lung cancer (NSCLC) therapy. However, the immunomodulatory influence of concurrent medications, including angiotensin-converting enzyme inhibitors (ACEIs), remains poorly defined in real-world practice. Methods: This retrospective observational study included 452 patients with metastatic NSCLC treated with first-line ICI-based therapy (ICI monotherapy or chemo-immunotherapy) between 2017 and 2025. Patients were stratified according to chronic ACEI exposure, defined as administration for >2 years. Primary endpoints were overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs). Results: Among 452 patients, 71 (15.7%) were chronic ACEI users. ACEI use was associated with significantly longer median OS in univariable analysis (17.0 vs. 14.0 months; HR = 0.78, 95% CI: 0.61–0.99; p = 0.047) and a favorable trend toward improved PFS (14.0 vs. 11.0 months; HR = 0.81, 95% CI: 0.64–1.02; p = 0.066). ACEI users had higher rates of cutaneous rash (25.4% vs. 13.1%; p = 0.011) and transaminase elevation (29.6% vs. 8.9%; p < 0.001). Severe grade 3–5 irAEs remained uncommon and did not differ significantly between groups (p > 0.05). Conclusions: Chronic ACEI use was associated with longer OS in univariable analysis, but this association was not statistically significant after multivariable adjustment. ACEI use was also associated with increased low-grade cutaneous and hepatic toxicities without a significant increase in severe irAEs. Prospective studies are warranted to clarify the clinical significance of these associations. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival below 5% for metastatic small cell lung cancer (SCLC) and below 10% for metastatic non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors have improved outcomes, but primary and acquired resistance, driven by tumor microenvironment immunosuppression, antigen heterogeneity, and T-cell exhaustion, leaves a substantial unmet need. T-cell engagers (TCEs), bispecific antibodies that redirect cytotoxic T-cells to tumor cells independent of MHC-I-restricted antigen presentation, offer a mechanistically distinct approach. Methods: We conducted a structured narrative review, without formal PRISMA methodology or meta-analytic pooling, of PubMed, Embase, and ClinicalTrials.gov through June 2026, supplemented by conference abstracts from ASCO, ESMO, AACR, and ATS, covering clinical, translational, and preclinical evidence for TCEs across established and emerging targets in thoracic malignancy. Results: Tarlatamab, a DLL3/CD3 bispecific TCE, received full FDA approval in November 2025 based on DeLLphi-304 data showing a median overall survival benefit of 13.6 versus 8.3 months over chemotherapy (HR 0.60; p < 0.001), establishing proof-of-concept for the TCE platform in lung cancer and NCCN Category 1 status in ES-SCLC. Beyond DLL3, an expanding pipeline of targets, including Claudin-18.2, TROP-2, FOLR1, CD70, and HER2, is under active TCE development; several of these antigens have independently validated tumor-selective expression through approved or late-stage antibody-drug conjugates (ADCs), providing target-level clinical de-risking for TCE development, though the two modalities have distinct requirements for antigen density and internalization that must be independently validated. Novel tri-specific constructs incorporating costimulatory domains and combination strategies with checkpoint inhibitors are in early clinical development. Conclusions: Tarlatamab approval validates the TCE platform in lung cancer, but overcoming TME-mediated resistance, antigen heterogeneity, and class-specific toxicities including cytokine release syndrome remains the central challenge. Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform’s impact in metastatic lung cancer. Full article

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Smoking is the primary etiological factor, but growing evidence suggests the involvement of estrogen in its development and progression, although its role remains unclear. This study explores: (i) the effects induced by estrogen, namely, 17β-estradiol (E2), alone or in combination with a mixture of inflammatory cytokines (Mix), in two human NSCLC cell lines, A549 and Calu1, and (ii) whether and how tumor cells can modulate the activation of normal lung fibroblasts. We found that E2 significantly enhances migration, invasion, and epithelial–mesenchymal transition in NSCLC cells, as well as their resistance to cisplatin, particularly in combination with Mix. Pharmacological inhibition of ERβ reversed the E2-induced effects, implicating ERβ in E2-mediated signaling. Furthermore, E2 increased autophagic flux and induced a shift toward secretory autophagy and the release of extracellular vesicles, which activated normal lung fibroblasts, as demonstrated by the increased expression of α-SMA, FAP, PDGFR-β, and PDPN. The clinical relevance of these data was supported by computational analyses revealing an elevated expression of the Mix gene signature, including TGF-β, IL-6, IL-8, CCXL-16, and ERβ, which was associated with shorter overall survival in NSCLC patients. This molecular profile was linked to the elevated expression of secretory autophagy genes and cancer-associated fibroblast markers. Validation in three large clinical cohorts (TCGA-LUNG, OAK and POPLAR) strengthens the clinical relevance of this E2-related pro-tumor axis while suggesting a promising therapeutic avenue for NSCLC patients. Full article

Background: Neoadjuvant chemoimmunotherapy has emerged as a standard option for resectable stage II–III non-small cell lung cancer (NSCLC); however, its impact on surgical feasibility, operative complexity, and perioperative outcomes remains incompletely characterized. We compared surgical feasibility, complexity, and perioperative outcomes across different neoadjuvant strategies. Methods: This single-center retrospective study included patients with stage II–III NSCLC who underwent curative-intent resection following neoadjuvant chemoimmunotherapy (neo-CIT), chemotherapy alone (neo-CT), or chemoradiotherapy (neo-CRT) during the same period. Surgical complexity was assessed using a four-level empirical grading scale. Perioperative outcomes, pathological response, and complications were compared among treatment groups using appropriate nonparametric statistical methods. Results: Twenty-four patients were included in the analysis (neo-CIT, n = 8; neo-CT, n = 12; neo-CRT, n = 4). R0 resection was achieved in 100%, 66.7%, and 75% of patients in the neo-CIT, neo-CT, and neo-CRT groups, respectively. Operative time, estimated blood loss, length of hospital stay, and overall postoperative complication rates did not differ significantly among groups. Thirty-day mortality was 0% in all groups, and 90-day mortality was 12.5% in the neo-CIT group and 0% in the neo-CT and neo-CRT groups. Surgical complexity scores were high across all cohorts and, when analyzed across the entire cohort, were not significantly associated with longer operative time (p = 0.16), greater blood loss (p = 0.83), or pathological response (p = 0.55). Neo-CIT was not associated with increased objective perioperative risk compared with neoadjuvant chemotherapy or chemoradiotherapy. Conclusions: In this single-institution exploratory analysis, neoadjuvant chemoimmunotherapy appeared to be surgically feasible and did not result in an apparent increase in perioperative risk compared with other neoadjuvant strategies. Although surgeons perceived increased operative complexity, objective perioperative risk remained acceptable when procedures were performed by experienced thoracic surgeons. However, given the limited sample size and lack of statistical power, these findings should be interpreted with caution and should not be considered evidence of equivalence. Full article

Background and Objectives: Transfusion-related immunomodulation (TRIM) is a recognized immunosuppressive phenomenon whose interaction with immune checkpoint blockade remains poorly defined. We evaluated the impact of erythrocyte suspension transfusion on survival and immune-related toxicity in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. Materials and Methods: This retrospective, multicenter study included 253 patients with metastatic NSCLC treated with nivolumab across five centers between April 2018 and March 2025. Patients who received a transfusion within three months before or during nivolumab therapy were compared with non-transfused patients. Survival was assessed using Kaplan–Meier and Cox regression analyses. Results: Forty-two patients (16.6%) received transfusion. Transfused patients had significantly shorter progression-free survival (PFS) (median 3.6 vs. 9.3 months; HR = 2.28, 95% CI 1.47–3.56, p < 0.001) and overall survival (OS) (median 5.8 vs. 16.3 months; HR = 2.76, 95% CI 1.86–4.11, p < 0.001). In multivariable analysis, transfusion was an independent predictor of both shorter PFS (HR = 2.288, 95% CI 1.470–3.561, p < 0.001) and shorter OS (HR = 2.351, 95% CI 1.565–3.533, p < 0.001), independent of transfusion volume. No statistically significant association was detected between transfusion status and the incidence of nivolumab-related toxicity (p = 0.585), although this analysis was likely underpowered, whereas nivolumab-related toxicity was an independent favorable prognostic factor. Conclusions: Erythrocyte transfusion independently predicted poorer survival but not immune-related toxicity in nivolumab-treated metastatic NSCLC, supporting more judicious transfusion practices during immunotherapy. Full article

Background/Objectives: Most cases of non-small cell lung cancer (NSCLC) are diagnosed at advanced stages, where prognosis remains poor. Machine learning (ML) offers new opportunities for patient stratification. This study aimed to identify distinct subgroups of patients with advanced-stage NSCLC using unsupervised ML techniques and to evaluate their association with survival outcomes and biomarker expression. Methods: 400 patients with advanced-stage NSCLC were analyzed using the k-prototypes algorithm. Clinical, demographic, and analytical variables, including smoking history and comorbidities, were incorporated. Identified clusters were compared in terms of molecular biomarkers and overall survival. A multivariable Cox proportional hazards model was performed to assess the association between cluster membership and overall survival. Results: Five patient profiles were identified. Cluster F, characterized by a predominance of women, relatively low smoking exposure, and a higher frequency of epidermal growth factor receptor (EGFR) mutations, showed the most favorable survival profile. Cluster S comprised mainly male heavy smokers with poorer performance status and high metastatic burden, whereas Cluster Y consisted predominantly of younger men without comorbidities but with frequent M1c disease. Clusters E and O showed intermediate outcomes and were characterized by older age with pleural effusion and by an older predominantly male smoking profile, respectively. In the multivariable Cox model, compared with Cluster F, a higher risk of death was observed for Cluster S (HR 1.62, 95% CI 1.01–2.60; p = 0.045) and Cluster Y (HR 1.55, 95% CI 1.09–2.21; p = 0.015), although the association for Cluster S should be interpreted cautiously. Differences in molecular biomarker distribution were also observed across clusters, particularly for EGFR mutations and programmed death-ligand 1 (PD-L1) expression. Conclusions: In this single-centre retrospective pilot study, unsupervised ML identified distinct patient profiles associated with differences in survival outcomes and molecular characteristics. These findings support the potential of data-driven approaches to characterize heterogeneity in advanced-stage NSCLC, although external validation is required before clinical application. Full article

The expansion of neoadjuvant immune checkpoint blockade, chemoimmunotherapy, and targeted therapies in oncogene-driven tumors is reshaping the management of resectable non-small cell lung cancer (NSCLC). Major pathologic response (MPR) and pathologic complete response (pCR), defined respectively as 10% or less residual viable tumor (RVT) within the primary tumor bed and the complete absence of viable tumor in both the resected primary tumor and sampled regional lymph nodes, have become widely adopted early efficacy endpoints. Both are consistently associated with favorable survival outcomes at the patient level, although their validity as trial-level surrogates for long-term outcomes remains incompletely established. Accurate pathologic response assessment requires rigorous standardization of gross specimen handling, tumor bed sampling, and microscopic quantification of viable tumor, necrosis, and stroma. International recommendations have improved methodological harmonization, and reproducibility studies have demonstrated good interobserver agreement when standardized protocols are applied. Increasing evidence also indicates that RVT behaves as a continuous prognostic variable and that integration of primary-tumor and nodal response may improve postoperative risk stratification. Beyond quantification of RVT alone, additional histologic characteristics of the residual tumor, together with stromal and immune therapy-related features, may provide complementary prognostic information. Digital pathology and artificial intelligence may support more reproducible quantitative assessment, whereas circulating tumor DNA-based molecular residual disease evaluation may capture systemic risk not represented by the resection specimen. These emerging approaches remain investigational and require prospective validation. This review critically examines the methodological standardization, biological interpretation, and prognostic validation of pathologic response in resectable NSCLC, and discusses future strategies integrating histopathologic, digital, and molecular variables into post-neoadjuvant risk assessment. Full article

Background: The interaction between COVID-19 vaccination and immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC) remains incompletely characterized. Methods: Retrospective cohort study of 139 patients with stage IV NSCLC treated with first-line ICI-based therapy, stratified by vaccination status and total doses received (0–1 vs. ≥2). Progression-free (PFS) and overall survival (OS) were analyzed by Kaplan–Meier and Cox regression; logistic regression explored factors associated with treatment-related toxicity. Results: Vaccinated patients had longer median PFS (13.0 vs. 11.0 months) and OS (29.0 vs. 24.0 months; both p < 0.001). In multivariable models these associations were attenuated and of borderline significance (OS HR = 0.83, 95% CI 0.69–0.99; PFS HR = 0.79, 95% CI 0.62–0.99). Outcomes were also more favorable with ≥2 doses (median PFS 14.0 vs. 12.0 months, p = 0.001; median OS 30.0 vs. 24.0 months, p < 0.001), and tumor mutational status was the strongest independent predictor of survival. In an exploratory model, ≥2 doses were associated with higher odds of any-grade toxicity (OR = 2.47, p = 0.037); events were predominantly low grade, with no Grade 4 or 5 toxicity. Conclusions: COVID-19 vaccination was associated with improved PFS and OS in stage IV NSCLC receiving first-line ICI therapy, with a dose-related pattern. The association was attenuated after adjustment for tumor biology and is hypothesis-generating. These findings support the safety and potential clinical relevance of vaccination in this population and underline the need for structured monitoring during immunotherapy. Prospective validation is required. Full article

Background/Objectives: Lung cancer remains one of the leading causes of cancer-related mortality worldwide. Conventional computed tomography (CT) is the preferred imaging modality for evaluating pulmonary nodules because of its high spatial resolution; however, it primarily provides morphological information, including lesion size, shape, and density. Dual-energy CT (DECT), a more recent imaging technique, uses two different energy levels to enable material decomposition and quantitative parameter assessment. These parameters may provide additional information regarding tumor perfusion, vascularization, and tissue composition. This rapid review aimed to evaluate the current evidence regarding the clinical utility of DECT in the detection, characterization, and staging of lung tumors. Methods: This rapid review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was performed in the PubMed and Cochrane Library databases for studies published between 2005 and 2026. Studies were included if they evaluated the detection, characterization, or staging of lung tumors using quantitative DECT parameters. Case reports, editorials, duplicate studies, and studies without quantitative DECT data were excluded. Descriptive data analysis was performed using Microsoft Excel. Results: A total of 24 studies were included, comprising 18 retrospective (75%) and 6 prospective studies (25%). Only one study evaluated the role of DECT in lung tumor detection, demonstrating improved detection of mixed ground-glass nodules and invasive adenocarcinoma. Significant correlations were found between iodine uptake and tumor perfusion, highlighting the potential of DECT to improve differentiation between benign and malignant lesions. Several studies also demonstrated associations between DECT parameters and tumor biomarkers, including Ki-67 Proliferation Index (Ki-67) expression, Epidermal Growth Factor Receptor (EGFR) mutation status, Programmed Death-Ligand 1 (PD-L1) expression, and treatment response in non-small cell lung cancer. In addition, DECT provided complementary metabolic information regarding tumor malignancy and showed correlations between iodine uptake and fluorodeoxyglucose (FDG) parameters. Associations between iodine volume and tumor differentiation grade were also reported. One study demonstrated the potential role of DECT in tumor staging by predicting mediastinal lymph node metastasis. Across all included studies, iodine-based parameters (50%), radiomics and material decomposition parameters (16.67% each), and spectral attenuation parameters (12.50%) were the most frequently investigated DECT metrics. Conclusions: DECT appears to be a promising complementary imaging technique that provides quantitative perfusion-related and compositional surrogate information beyond the morphological assessment offered by conventional CT. However, the current evidence remains heterogeneous and is largely based on retrospective studies with relatively small patient cohorts. Larger prospective studies with standardized imaging protocols are necessary to further establish the clinical utility of DECT in lung tumors. Full article

Background: Immune checkpoint inhibitors (ICIs) have moved from the metastatic setting into neoadjuvant, adjuvant, and fully perioperative strategies across several solid tumors. This shift has created a new clinical interface between medical oncology, surgery, anesthesia, pathology and postoperative care because immune activation may improve pathological response and survival while also generating immune-related adverse events (irAEs) that mimic or aggravate perioperative complications. Methods: We conducted a scoping review according to PRISMA-ScR. PubMed/MEDLINE and Web of Science were searched for studies published between 2016 and 2026 that evaluated adult patients with solid tumors receiving ICIs in relation to surgery. Thirty-three studies were included and synthesized descriptively across surgical feasibility, perioperative safety, irAEs, anesthetic considerations, and oncological outcomes. Results: The strongest evidence was found in resectable non-small-cell lung cancer, where neoadjuvant or perioperative ICI-based regimens improved pathological response and, in several trials, event-free or overall survival. Evidence in triple-negative breast, bladder, gastric/gastroesophageal junction, and ovarian cancers supported broader applicability but remained heterogeneous, with variable efficacy across tumor types and treatment regimens. Surgery following ICI exposure was generally feasible, without a consistent increase in postoperative mortality. However, pneumonitis, myocarditis, endocrinopathies, hepatitis, colitis, and cytokine release syndrome may mimic conventional postoperative complications. Direct evidence comparing anesthetic or perioperative management strategies was scarce. Conclusions: Perioperative ICI-based therapy is no longer an experimental concept, but its safe implementation requires structured preoperative screening, individualized surgical timing, organ-specific toxicity surveillance, careful corticosteroid decision-making, and close multidisciplinary communication. Future prospective studies should integrate standardized perioperative endpoints, anesthesia-related variables, biomarker-driven risk stratification, and long-term oncological outcomes. Full article

Background: Anatomical segmentectomy has increasingly emerged as an accepted surgical strategy for selected patients with early-stage non-small cell lung cancer (NSCLC), particularly following the JCOG0802/WJOG4607L and CALGB/Alliance 140503 randomized trials. Although these studies demonstrated oncologic equivalence—or even superiority in overall survival—compared with lobectomy in carefully selected tumors, concerns persist regarding increased locoregional recurrence after segmentectomy. Recent evidence suggests that recurrence is influenced not only by surgical technique but also by tumor biology, radiological characteristics, nodal assessment, and patient-specific factors. Methods: This narrative review critically summarizes contemporary evidence regarding local recurrence after anatomical segmentectomy for early-stage NSCLC. A literature review was performed using PubMed/MEDLINE database and recent thoracic surgical literature published primarily from 2015 onwards. Randomized trials, prospective and retrospective studies, meta-analyses, and expert consensus statements were included, with particular focus on recurrence patterns, tumor biology, radiological features, surgical factors, lymph node assessment, and emerging technologies. Results: Segmentectomy provides comparable overall survival to lobectomy in selected patients with small peripheral NSCLC; however, locoregional recurrence remains more frequent after segmentectomy. Major predictors of recurrence include pure-solid radiological appearance, high consolidation-to-tumor ratios, larger tumor size, STAS positivity, lymphovascular invasion, aggressive adenocarcinoma subtypes, inadequate lymph node assessment, and insufficient surgical margins. Hypermetabolic tumors on PET imaging and occult nodal disease further increase recurrence risk. Several studies identified delayed recurrence patterns occurring beyond 5 years after surgery. Conclusions: Local recurrence remains the principal oncologic limitation of segmentectomy. Contemporary evidence supports a shift from size-based toward biology-driven surgical decision-making integrating tumor morphology, metabolic activity, histopathological aggressiveness, STAS status, and nodal involvement into surgical planning. Full article