8002 Background: While adjuvant alectinib has established itself as the new standard for resected anaplastic lymphoma kinase (ALK) fusion non-small cell lung cancer (NSCLC), there is limited data on neoadjuvant treatment for locally advanced ALK fusion NSCLC. Given the groundbreaking efficacy of lorlatinib in advanced NSCLC, it is worth exploring its clinical feasibility as neoadjuvant treatment for stage III ALK+ NSCLC. Methods: This study is an open-label, phase 2 multi-center prospective trial (ClinicalTrials.gov NCT05740943) utilizing a Simon two-stage design. Patients diagnosed with potentially resectable or unresectable stage III ALK+ NSCLC were enrolled, with up to 3 cycles of lorlatinib administered, followed by optional local treatment and consolidation lorlatinib for up to 2 years. The primary endpoint was the pathological complete response (pCR) (H0≤20%, H1≥40%, α=0.05, β=0.2, at least 12 pCR events for 43 patients enrolled), while secondary endpoints included major pathological response (MPR), event-free survival (EFS), overall survival (OS), and safety profile. Xenium as well as spatial proteomics was performing on paired samples collected before and after lorlatinib. Results: As of January 1, 2026, 43 patients with stage III ALK-fusion NSCLC (19 evaluated as potentially resectable and 24 as unresectable) were consecutively enrolled and received 3 cycles neoadjuvant lorlatinib, with 32 completing surgery (including neck dissection and/or contralateral lymph node dissection), 9 continuing TKI therapy, and 2 undergoing radiotherapy. The most common treatment-related adverse events (TRAEs) included hypertriglyceridemia, hypercholesterolemia, and edema. The confirmed objective response rate (ORR) was 83.7% (36/43), without progressive disease (PD). Among patients who underwent surgery, the R0 resection rate was 96.9% (31/32) and 3 patients experiencing conversion to thoracotomy. pCR and MPR rates were 46.9% (15/32) and 81.3% (26/32), respectively, reaching the primary endpoint. Pathological nodal downstaging was seen in 90.6% (29/32) patients. For those with initially unresectable stage III disease, 75.0% (18/24) achieved conversion surgery through multidisciplinary evaluation after neoadjuvant lorlatinib, while others continued TKI or underwent radiotherapy. With a median follow-up of 13 months, the 1-year EFS rate was 97.1% (95% CI, 91.5-100) and no OS events were observed. Only 3 patients experienced local relapse (regional lymph nodes and/or intrapulmonary metastasis) without distant metastasis; all had initially presented with N3 disease and did not receive adjuvant lorlatinib after surgery. Conclusions: Neoadjuvant lorlatinib unveiled overwhelming pathological response and could lead to high conversion surgery for unresectable stage III disease. Further large-scale prospective trial was warranted to testified such treatment modality. Clinical trial information: NCT05740943 .

Epidermal growth factor receptor-mutated (EGFR-M+) non-small-cell lung cancer (NSCLC) represents a substantial proportion of lung cancer and remains associated with a considerable risk of postoperative recurrence despite advances in targeted therapies. The role of programmed death-ligand 1 (PD-L1) expression in the perioperative treatment of EGFR-M+ NSCLC remains controversial. The gene mutation landscape of PD-L1 in EGFR-M+ NSCLC and its relationship with prognosis remain poorly understood. We retrospectively included patients with EGFR-M+ NSCLC, including 43 patients with stage IB–IV disease who underwent immunotherapy combined with chemotherapy followed by surgery (NeoGroup) and 499 patients with stage IB–III disease undergoing surgery (AdjGroup). Disease-free survival, radiological response, pathological response, clinicopathological factors, and genomic characteristics were analyzed to evaluate their associations with PD-L1 tumor proportion score (TPS). The NeoGroup had objective response, pathological complete response, and major pathologic response rates of 44.2

Cells must adopt flexible regulatory strategies to make decisions regarding their fate, including differentiation, apoptosis, or survival in the face of various external stimuli. One key cellular strategy that enables these functions is stochastic gene expression programs. However, understanding how transcriptional bursting, and consequently, cell fate, responds to DNA damage on a genome-wide scale poses a challenge. In this study, we propose an interpretable and scalable inference framework, DeepTX, that leverages deep learning methods to connect mechanistic models and single-cell RNA sequencing (scRNA-seq) data, thereby revealing genome-wide transcriptional burst kinetics. This framework enables rapid and accurate solutions to transcription models and the inference of transcriptional burst kinetics from scRNA-seq data. Applying this framework to several scRNA-seq datasets of DNA-damaging drug treatments, we observed that fluctuations in transcriptional bursting induced by different drugs were associated with distinct fate decisions: 5′-iodo-2′-deoxyuridine treatment was associated with differentiation in mouse embryonic stem cells by increasing the burst size of gene expression, while low- and high-dose 5-fluorouracil treatments in human colon cancer cells were associated with changes in burst frequency that corresponded to apoptosis- and survival-related fate, respectively. Together, these results show that DeepTX enables genome-wide inference of transcriptional bursting from single-cell transcriptomics data and can generate hypotheses about how bursting dynamics relate to cell fate decisions.

INTRODUCTION:Evaluation of molecular residual disease (MRD) status in patients with NSCLC after surgery primarily relies on circulating tumor DNA (ctDNA) analysis. However, given the narrow postoperative window (4-6 wk) for adjuvant therapy, the approximately 70% false-negative rate of single-time point ctDNA landmark detection severely limits its utility. METHODS:Here, we introduce LAMPAD, an XGBoost-Cox model that incorporates an additional preoperative time point alongside the standard postoperative landmark. By leveraging ctDNA quantification from both time points, it refines prognostic stratification among patients with landmark undetectable MRD, specifically identifying those who are truly disease free. RESULTS:The LAMPAD model, incorporating the top five features ranked by Shapley additive explanations analysis-baseline ctDNA level, TNM stage, landmark cell-free DNA (cfDNA) concentration, baseline cfDNA concentration, and baseline ctDNA status-was trained on 163 patients with stages I to III NSCLC with landmark undetectable MRD. The model effectively stratified patients into low-risk (2-y disease-free survival [DFS]: 97.8%) and high-risk (2-y DFS: 71.6%) groups (hazard ratio = 0.11, 95% confidence interval: 0.06-0.21, p < 0.001). LAMPAD demonstrated consistent performance across both fixed-panel and personalized ctDNA-MRD approaches in multiple validation NSCLC cohorts (pooled 2-y DFS: 94.3% versus 72.4% for low- versus high-risk groups; hazard ratio = 0.18, 95% confidence interval: 0.13-0.25, p < 0.001). Preoperative blood test markedly contributed to the LAMPAD model, with methylation analysis revealing elevated immune-derived and lung-derived cfDNA in high-risk patients, suggesting systemic immune involvement in risk stratification. CONCLUSIONS:Overall, the LAMPAD model outperforms single-time point postoperative ctDNA detection by effectively discriminating true negative patients, thereby offering a more reliable prognostic tool for identifying low-risk patients with potential for cure.

Background:To evaluate the efficacy and safety of neoadjuvant sintilimab, a programmed cell death 1 protein (PD-1) blockade combined with chemotherapy in patients with resectable stage II-IIIB epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). Methods:This was a single-arm, open-label, phase II trial (CTONG2104) conducted in China. Patients with resectable stage II-IIIB EGFR (AJCC 8th edition) mutant NSCLC were enroled and received neoadjuvant sintilimab (200 mg) plus carboplatin (area under the curve 5) and nab-paclitaxel (260 mg/m2) for 3 cycles. Patients in stage II cohort received adjuvant osimertinib for up to 2 years while observation for stage I cohort. The primary endpoint was major pathological response (MPR) rate (per IASLC criteria) in patients who received at least one dose neoadjuvant sintilimab plus chemotherapy. Secondary endpoints included pathological complete response (pCR) rate (per IASLC criteria), objective response (ORR) rate (per RECIST), event-free survival (EFS), overall survival (OS) and safety profile in all enroled patients. This study is registered with ClinicalTrials.gov, NCT05244213. Findings:Between May 10, 2022, and March 20, 2024, 35 eligible patients (median [range] age, 60 [48-73] years; 18 [51.4%] female) were enroled and received neoadjuvant treatment and 33 (94.3%) completed surgical resection. The median follow-up was 33.7 months. The primary endpoint was met, with a MPR following neoadjuvant immunochemotherapy of 34.3% (95% CI 19.1-52.2). The ORR and pCR was 60.0% and 11.4%, respectively. Patients with RB1 or RBM10 co-mutations respond well to neoadjuvant immunochemotherapy while opposite for EGFR tyrosine kinase inhibitors (TKIs). The median EFS was not reached with 2-year EFS rate of 71.4% (95% CI 57.9-88.1%). The safety profile during neoadjuvant treatment was tolerable, with 29% of patients experiencing grade 3-4 adverse events. All patients underwent minimally-invasive surgery with 87.9% achieved R0 resection. 42.9% patients experienced local relapse and oligo-metastasis, respectively and 81.8% achieved objective response after receiving EGFR-TKIs. Interpretation:Neoadjuvant sintilimab plus chemotherapy revealed encouraging clinical and pathological response with well tolerability in EGFR-mutant NSCLC. Upfront immunochemotherapy did not add sever immune toxicity or impact response rate to TKIs for adjuvant or first-line osimertinib. Further study with randomized controlled design is warranted to verified such treatment modality. Funding:Innovent Biologics (Suzhou) Co., Ltd. provided PD-1 regimen (sintilimab), participant compensation and insurance. This work was supported by National Science Foundation of China, Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China National High-Level Talents Special Support Program, National Natural Science Foundation of China Major Joint Project on Key scientific issues of lung Cancer, Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer, Integrated Project of Major Research Plan of National Natural Science Foundation of China, National Health Commission Medical and Health Technology Development Research Centre Project.

Aims:Alectinib was approved by the US, Europe and China in 2024 as the first adjuvant targeted therapy for ALK+ NSCLC, lowering risk of disease recurrence or death by 76%. Alectinib addresses a critical gap in postoperative adjuvant therapy for ALK+ NSCLC. From Chinese healthcare-system perspective, this study evaluates the impact of introducing alectinib in adjuvant therapy for stage IB (tumor ≥ 4 cm) to IIIA (UICC/AJCC 7th edition) ALK+ NSCLC on prevention of recurrence and the associated direct medical costs, compared to platinum-based chemotherapy. Methods:A Markov model was developed to estimate the number of locoregional and metastatic recurrences over a 10-year period by defining four health states: disease-free survival, locoregional recurrence, metastatic recurrence, and death. In the control group, all patients received platinum-based chemotherapy, while in the intervention group, 75% received alectinib and 25% received platinum-based chemotherapy. Clinical data were collected from open-label, randomized phase 3 trials ALINA and ALEX. Cost parameters were derived from local charges, expert consultation, and published literature. Results:Compared to control group, the intervention group would reduce recurrences by 11,300 cases over 10 years, including 3,684 locoregional and 7,616 metastatic cases. This corresponds to a 45.82% lower recurrence rate. Estimated recurrence-related cost savings amounted to 6.910 billion RMB, with 1.445 billion RMB saved from locoregional recurrences and 5.465 billion RMB from metastatic recurrences. This represents a 41.49% reduction in costs compared to control group. These findings were robust across various scenario analyses. Conclusion:Using alectinib in postoperative adjuvant therapy significantly reduces both the recurrence rate and recurrence-related treatment costs for stage IB (tumor ≥ 4 cm) to IIIA ALK+ NSCLC patients, compared to platinum-based chemotherapy. From perspective of Chinese healthcare system, this approach shows substantial potential for preventing recurrence and achieving cost savings.

The prognosis of non-small cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is dismal. The regulators of LM progression remain elusive, thus impeding effective clinical intervention. Here, we performed in vivo genome-wide CRISPR-based screens and found that fused in sarcoma (FUS) ablation promoted LM in both PC9 and A549 cells. FUS repressed CD36 expression by directly interacting with and destabilizing PPARA (peroxisome proliferator-activated receptor α) messenger RNA. CD36 augmented fatty acid uptake and oxidative phosphorylation in NSCLC cells. Matrix metallopeptidase 2 (MMP2) was up-regulated through CD36-mediated fatty acid metabolism, which enabled NSCLC cells to disrupt the endothelial barrier. FUS-deficient NSCLC cells increased the expression of neuroendocrine differentiation (NED)-related markers, including SRY-box transcription factor 2 (SOX2), microtubule-associated protein 2 (MAP2), enolase 2 (NSE), and synaptophysin (SYP). They also exhibited neurite-like extensions and expanded in cerebrospinal fluid-supplemented medium in a CD36-dependent manner. Mechanistically, fatty acid uptake increased acetyl-coenzyme A and H3K27ac modifications to promote the expression of NED signature genes and MMP2 in NSCLC cells. Genetic or pharmacological inhibition of CD36 or inhibition of NED-related markers in NSCLC cells hindered LM and prolonged survival in mice. In patients with NSCLC, down-regulation of FUS or up-regulation of CD36 or SYP was associated with progression to LM. Thus, CD36-mediated fatty acid metabolism and NED signature are crucial for progression to LM in NSCLC, highlighting CD36 as a promising therapeutic target to limit the progression of LM.

OBJECTIVES:Neoadjuvant immunotherapy is the standard of care for resectable non-small cell lung cancer (NSCLC); however, the impact of adjuvant immunotherapy (adj-IO) remains to be elucidated. In this study, we aimed to explore the impact of adj-IO on survival of patients who underwent neoadjuvant immunotherapy for stage II-IIIB NSCLC. MATERIALS AND METHODS:We retrospectively collected data of patients who received neoadjuvant immunotherapy followed by complete resection for stage II-IIIB NSCLC from January 2019 to August 2023 in Guangdong Provincial People's Hospital (China). The non-adj-IO group was matched 1:1 with the adj-IO group via propensity score matching (PSM). Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier analysis and compared using the log-rank test. The impact of adj-IO on survival was assessed via Cox regression analysis. RESULTS:This study included 267 patients. After PSM, the final cohort comprised 102 patients per group (median [range] age: 60 [25-82] years; 168 male). Patients who received adj-IO had a similar DFS (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.65-1.88, P = 0.705) and OS (HR: 0.47, 95% CI: 0.21-1.06, P = 0.070) to those without adj-IO. In subgroup analyses, adj-IO did not improve DFS or OS in terms of pathological response, the programmed death-ligand 1 (PD-L1) expression level (PD-L1 = 0% vs. others), or the histological subgroup (adenocarcinoma vs. others). Adj-IO was not an independent prognostic factor for DFS (P = 0.427) or OS (P = 0.210). CONCLUSION:Adj-IO may have no impact on survival in patients who undergo complete resection after neoadjuvant immunotherapy and may be omitted in perioperative immunotherapy.

8509 Background: Neoadjuvant target therapy has improved objective response rate (ORR) or major pathological response (MPR) of stage IIA-IIIB non-small cell lung cancer (NSCLC) with EGFR mutation. EGFR-TKI-induced evolution indicated a hot-tumor status in residual disease. However, the role of immunotherapy in this phrase remained unclear. Here, we present the results of a phase II, open-label study investigating the efficacy and safety of sequential almonertinib and chemo-immunotherapy (IO) in potentially resectable stage IIA-IIIB EGFR-mutant NSCLC patients. (NCT06300424). Methods: Untreated patients with II-IIIB NSCLC were enrolled in this study. Patients received almonertinib for 6 weeks, followed by 3 cycles of adebrelimab and chemotherapy before surgery. Primary end point was MPR, Secondary end points included pathological complete response (PCR), ORR, event-free survival (EFS), overall survival (OS) and safety. Results: A total of 32 patients were enrolled from Apr 2024 to Aug 2025. EGFR mutation subtype was 19del in 16 (50.0%) patients, L858R in 11 (34.4%) patients, others in 5 (15.6%) patients. All the patients completed neoadjuvant almonertinib, 30 (93.8%) patients completed 3 circles of chemo-IO and underwent surgery, R0 was achieved in 29 (96.7%) patients. ORR was 46.9% (15/32) and 59.4% (19/32) after target therapy and chemo-IO, respectively. MPR was documented in 13 (40.6%) patients, including PCR in 5 (15.6%) patients. In patients underwent resection, MRP and PCR rate were 66.7% and 33.3% in patients with PD-L1≥1%, compared with 21.4% and 0% in PD-L1 ＜1% subgroup, respectively, N downstage was confirmed in 44.8% (13/29) patients. After a median follow-up of 13.5 months (interquartile range [IQR], 7.5–16.1 months), 31 (96.9%) patients were alive. Median EFS and OS were not reached. One-year EFS and OS rate was 89.5% and 95.2%, respectively. Grade ≥ 3 AEs occurred in 28 (87.5%) patients during neoadjuvant therapy. Conclusions: This study met its primary endpoint, indicating almonertinib followed by chemo-IO was a feasible neoadjuvant treatment in patients with resectable stage IIA-IIIB EGFR-mutant NSCLC, especially in patients with PD-L1 expression. The study was partially supported by Jiangsu Hengrui Pharmaceuticals and Hansoh Pharmaceutical Group Co. Ltd. Clinical trial information: NCT06300424 . Primary and secondary outcomes. Outcomes ITT (N=32) Resection (N=29) Major pathological response rate 40.6% (13/32) 44.8% (13/29) PD-L1＜1% 18.8% (3/16) 21.4% (3/14) PD-L1≥1% 62.5% (10/16) 66.7% (10/15) Complete pathological response rate 15.6% (5/32) 17.2% (5/29) PD-L1＜1% 0.0% (0/16) 0.0% (0/14) PD-L1≥1% 31.3% (5/16) 33.3% (5/15) After receiving neoadjuvant TKI ORR 46.9% (15/32) 44.8% (13/29) DCR 93.8% (30/32) 96.6% (28/29) After receiving neoadjuvant TKI+IO ORR 59.4% (19/32) 58.6% (17/29) DCR 100.0% (32/32) 100.0% (29/29) TKI: Tyrosine kinase inhibitor; IO: Immunotherapy.

Objective This study aims to compare postoperative survival outcomes between pathological stage IA pulmonary invasive mucinous adenocarcinoma (IMA) and invasive non-mucinous adenocarcinoma (INMA) and assess the effectiveness of sublobar resection in patients with stage IA IMA. Methods This study analyzed 113 patients with resected stage IA IMA (2015–2022) and 364 patients with resected stage IA INMA (2015–2019) from Guangdong Provincial People's Hospital. Propensity score matching (PSM) was applied to balance baseline characteristics. Survival curves were generated using the Kaplan–Meier method, and differences were evaluated with log-rank tests. Cox regression analysis was performed to identify predictors of survival. Results Before PSM, the IMA cohort exhibited a higher proportion of lower lobe foci (60.2 % versus 32.7 %; p < 0.001), a greater prevalence of stage IA1 disease (25.7 % versus 8.52 %; p < 0.001), and a lower frequency of sublobar resections (26.5 % versus 45.1 %; p = 0.001). Survival analysis demonstrated significantly reduced recurrence-free survival (RFS) and overall survival (OS) in patients with stage IA IMA compared to those with INMA (before PSM: RFS, p = 0.01; OS, p < 0.001; after PSM: RFS, p = 0.034; OS, p = 0.014). Pathological subtype and spread through air spaces were identified as independent predictors of RFS. Within the IMA group, statistically non-significant differences were observed between sublobar resection and lobectomy (before PSM: RFS, p = 0.17; OS, p = 0.27; after PSM: RFS, p = 0.71; OS, p = 0.37). Conclusion Patients with stage IA IMA exhibited inferior survival outcomes compared to those with stage IA INMA. No significant survival difference was observed between sublobar resection and lobectomy in patients with stage IA IMA.

Leptomeningeal metastasis (LM) is a devastating complication of non-small cell lung cancer (NSCLC), yet timely diagnosis remains challenging because conventional approaches, including magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology, have limited sensitivity, particularly at initial presentation. Small extracellular vesicles (sEVs), as nanoscale carriers of protected regulatory cargo, have emerged as promising substrates for liquid biopsy. However, in anatomically compartmentalized central nervous system malignancies, the extent to which disease-associated sEV-miRNA signals are preserved across biofluids remains unclear. We profiled sEV-associated miRNAs by small RNA sequencing in CSF and plasma samples from NSCLC patients with clinically adjudicated LM status (NC, LM−, and LM+), including paired specimens where available. Biofluid-specific miRNA programs were characterized using weighted gene co-expression network analysis (WGCNA), and diagnostic models were developed using machine learning with Random Forest and LASSO-based feature selection. Model performance was evaluated in an independent validation cohort relative to final adjudicated LM status and compared with initial and cumulative MRI and CSF cytology assessments. CSF-derived sEV-associated miRNAs showed markedly stronger disease-stratification capacity than plasma-derived signals (ARI = 0.813 vs. 0.255; cluster purity = 0.868 vs. 0.694), revealing profound biofluid asymmetry. Network analysis identified a dominant LM-associated module in CSF (r = 0.74, P = 9 × 10⁻⁷) with limited preservation in plasma, indicating that LM-related vesicle-associated molecular programs are compartment-restricted. From this CSF-specific nanoscale vesicle signature, we derived a four-miRNA diagnostic panel comprising hsa-let-7e-5p, hsa-miR-30d-5p, hsa-miR-486-5p, and hsa-miR-375. In the independent validation cohort, the single-sample sEV-miRNA panel achieved an AUC of 0.935, with 86.4

BACKGROUND:Immune checkpoint inhibitors have improved outcomes for several malignancies; however, there remains a lack of accurate, non-invasive methods to assess tumor PD-L1 expression levels and guide immunotherapy. This study aimed to evaluate the role of PD-L1-targeted positron emission tomography (PET) imaging in predicting immunotherapy response and prognosis in lung cancer. METHODS:Four healthy volunteers and 22 treatment-naïve lung cancer patients were prospectively enrolled and underwent [68Ga]Ga-PDL1p PET imaging. All patients additionally completed paired baseline [18F]fluorodeoxyglucose ([18F]FDG) PET scans. Of the 22 patients, 17 received ≥3 cycles of immunotherapy combined with chemotherapy and underwent follow-up [18F]FDG PET or CT examinations. The correlations of baseline [68Ga]Ga-PDL1p and [18F]FDG uptake with tumor PD-L1 expression were evaluated. Furthermore, the associations of tumor [68Ga]Ga-PDL1p uptake, [18F]FDG uptake, and PD-L1 expression with immunotherapy response were analyzed, along with their predictive values for immunotherapy efficacy and outcomes. RESULTS:Lesions with high PD-L1 expression exhibited significantly higher [68Ga]Ga-PDL1p uptake than those with low expression (p=0.007), whereas [18F]FDG uptake showed no significant difference (p=0.499). At baseline, [68Ga]Ga-PDL1p uptake was significantly higher in responders than in non-responders (p=0.008), with an area under the receiver operating characteristic curve of 0.886. In contrast, neither [18F]FDG uptake nor PD-L1 expression levels differed significantly between the two groups. Disease progression occurred in 23.5% of patients (4/17) by the final follow-up. Patients with higher [68Ga]Ga-PDL1p uptake or higher [18F]FDG uptake demonstrated significantly longer progression-free survival (PFS) than those with lower uptake (p=0.033 and p<0.001, respectively). However, no significant difference in PFS was observed between patients with high and low PD-L1 expression, using either a 50% (p=0.487) or 1% (p=0.100) cut-off. CONCLUSIONS:[68Ga]Ga-PDL1p PET outperforms conventional [18F]FDG PET and immunohistochemistry-based PD-L1 assessment in predicting immunotherapy response and prognosis. These findings offer new insights for evaluating immunotherapy efficacy and guiding individualized tumor treatment.

Background The benefit of local consolidative therapy (LCT) in advanced non-small cell lung cancer (NSCLC) following first-line systemic treatment remains controversial. This study integrated circulating tumor DNA (ctDNA), genomic, and transcriptomic data to address three critical clinical questions: how to identify the most suitable advanced NSCLC patients for LCT, how to determine the optimal timing for implementing LCT, and whether systemic treatment strategies should be modified after LCT. Methods In this prospective study (NCT05648370), patients with induced oligometastatic NSCLC (previous history of polymetastatic disease thatconverted to an oligometastatic disease during systemic therapy, with a median treatment duration of 7.5 months [range: 2–41]) who received first-line systemic therapy. According to physician assessment, the patients were stratified into an LCT group (receiving surgery) and a non-LCT group (continuing systemic therapy). In the LCT group, high-depth ctDNA monitoring was performed both before and after LCT, and whole-exome and transcriptome sequencing were conducted when tumor tissue samples were available. Progression-free survival (PFS) and overall survival (OS) was compared between the two groups. Results A total of 127 patients with induced oligometastatic NSCLC were included for final analysis. The LCT group (n = 71; median PFS, 28.1 months; median OS, not reached) had better survival benefits than the non-LCT group (n = 56; median PFS, 15.8 months; median OS, 38.5 months) (P < 0.001). Importantly, within the LCT cohort, a distinct subgroup of patients with favorable outcomes was identified and termed molecular oligometastatic disease (MOD), defined as induced oligometastatic NSCLC with undetectable ctDNA after systemic therapy and before LCT. MOD was characterized by lower genomic tumor burden, and reduced genomic and transcriptomic activation of cell proliferation pathways. Patients with MOD who underwent LCT achieved significantly longer overall and post-LCT PFS than non-MOD patients (P < 0.001). Furthermore, clinical multivariate analysis identified that systemic therapy duration and MOD status as independent predictors of PFS, suggesting that both factors should be considered when determining the optimal timing for LCT. By integrating surgical pathology, ctDNA dynamics, gene expression signatures, and survival outcomes, we found that patients exhibiting resistance-related features or an immune-depleted tumor microenvironment had poorer prognosis and might benefit from switching systemic therapy after LCT. Conclusions MOD defines a distinct subtype of advanced NSCLC with less aggressive clinical and molecular characteristics, which derive maximal benefit from LCT. The timing of LCT should consider both treatment duration and MOD status. Patients with resistance-related features or immune-depleted tumor microenvironments may require a systemic therapy switch following LCT. This study is limited by the single-center design and relatively limited sample size, and may require prospective validation in larger multicenter cohort studies and randomized controlled trials.

Background: Chest tube placement after pulmonary resection has been conventionally recommended, yet the associated patient discomfort can hinder postoperative recovery. In previous work, we demonstrated that catheter drainage is a safe alternative to conventional chest tube following wedge resection and provides superior pain relief. This study aims to evaluate whether a complete tubeless strategy offers further advantages compared to catheter drainage. Methods: We conducted a retrospective cohort study and enrolled patients who underwent video-assisted thoracoscopic surgery (VATS) pulmonary wedge resection at our institution between September 2020 and November 2024. Participants were categorized into a catheter drainage group or a tubeless group based on the absence of postoperative thoracic drainage. Propensity score matching (PSM) was applied in a 1:1 ratio to balance baseline characteristics. Univariate analysis was then used to compare operative outcomes and perioperative complications between the matched groups. Results: Of the 460 initially eligible patients, 133 matched pairs were generated after PSM. The tubeless group demonstrated a significantly shorter operative duration (57.00 vs. 80.00 min, P<0.001) and lower postoperative pain scores [Numerical Rating Scale (NRS): 0.00 vs. 2.00, P<0.001] than the catheter group. No significant differences were observed in the incidence of postoperative complications, rates of reintubation, or length of postoperative hospital stay. Conclusions: Omitting thoracic drainage entirely is a feasible and advantageous approach for a highly selected subset of patients undergoing pulmonary wedge resection. In this selected cohort, the tubeless strategy is associated with diminished postoperative pain and enhanced patient satisfaction, without increasing perioperative risks. The observed reduction in operative time is likely confounded by patient selection factors and should not be interpreted as a direct benefit of the technique. These findings support its consideration in patients intraoperatively assessed as low-risk; however, the observed benefits should be interpreted in the context of the stringent selection criteria applied, which may limit generalizability.

Determining tumor progression status is critical for early-stage lung adenocarcinoma (esLUAD) diagnosis and treatment, yet histopathology-based grading often overlooks heterogeneity within grades. We propose RadioTrace, a deep contrastive learning framework integrating radiomic and pathological information to learn a radiomic trajectory for quantifying esLUAD progression. Across four multi-institutional cohorts, RadioTrace well predicted tumor phenotypes including spread through air spaces (STAS) and lymph node metastasis (LNM). Survival analyses demonstrated it as an independent prognostic factor (log-rank test p < 0.004 across all cohorts). Within the same pathological grade, it revealed significant survival heterogeneity (p < 0.02 across all cohorts), underscoring the limitations of current grading criteria. Genomic and transcriptomic analyses confirmed associations with progression-related molecular features. Longitudinal analysis of patients with multiple CT follow-ups further showed consistency with continuous progression. These findings demonstrate that RadioTrace enables quantitative, interpretable assessment of esLUAD progression, providing insights beyond histopathology and assisting clinical decision-making.

Background Brain metastases (BrM) in non-small cell lung cancer (NSCLC) present a significant challenge due to poor prognosis. While immune checkpoint inhibitors (ICIs) have been standard treatments for NSCLC, their efficacy in BrM is variable, emphasizing the urgent need for predictive biomarkers and fundamental mechanisms.Methods Patients with NSCLC and BrM planning to receive ICI therapy were enrolled in the prospective cohort, dynamic cerebrospinal fluid (CSF) samples (n=20) were collected through lumbar puncture and used for single-cell RNA sequencing (scRNA-seq), and BrM tumors were collected if they have the indications of surgery, with integrating scRNA-seq data from external database (total n=20). Three independent cohorts underwent flow cytometry (n=8), proteomics analysis (n=31), and multiplex immunohistochemistry (n=25) for validation.Results Our study provided a high-resolution atlas of cellular dynamics in the CSF and BrM during ICI therapy in patients with NSCLC and BrM. Notably, we identified a key immune cell subset, CD4+PDCD1+CXCR6+ T cells, as a positive predictor of ICI intracranial tumor responses, which presented highly functional and transcriptomic similarities in both CSF and BrM tumor environment. Moreover, CXCR6 could serve as a specific marker for CD4+PDCD1+ T cells linked to ICI response. Further, we revealed that the novel cluster of CD4+PDCD1+CXCR6+ T cells was closely associated with lymphocyte activation and aggregation in CSF and BrM of ICI responders, and classical dendritic cells of ICI responders interacted with CD4+PDCD1+CXCR6+ T cells for enhanced antigen presentation and inflammatory activation.Conclusion Our findings revealed critical insights into the immune landscape of NSCLC BrM under ICI therapy, highlighting CD4+PDCD1+CXCR6+ T cells in CSF as a promising biomarker and illuminating fundamental mechanisms underlying ICI efficacy.

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.

The effects of the tumor microenvironment the therapeutic efficacy of combining chemotherapy with checkpoint inhibitors in patients with lung cancer harboring rare -driver mutations remain unclear. We utilized single-cell RNA- and T-cell receptor (TCR) -sequencing to explore the immune and stromal cell profiles of 12 tumors and five tumor-adjacent tissues in seven patients with non-small cell lung cancer (NSCLCs) with rare -driver mutations treated with anti-PD-1 agents combined with chemotherapy. A class of highly expanded T -cells, known as GZMK + CD8+ effector memory T cells (GZMK + CD8+Tem), was enriched in both responsive tumors with and without rare driver mutations, suggesting similar anti-tumor immune mechanisms in both cohorts and that high levels of GZMK + CD8+Tem might be associated with effective responses to combination therapy. Non-responsive tumors exhibited a highly immunosuppressive M2-phenotype with enriched macrophages and monocytes. In non-major pathological response tumors, tumor cells interacted with alveolar and M0 macrophages via LAMC2-(ITGA6+ITGB1), possibly leading to M2 polarization. OAS1 was specifically expressed in CHIT1+ and FABP4+ macrophages and promoted macrophage polarization. These findings suggest that combination therapy reprogramed alveolar and M0-like macrophages to a pro-tumor phenotype, creating an immunosuppressive tumor microenvironment that resisted anti-PD1 therapy. In conclusion, GZMK + CD8+Tem is crucial for effective responses, whereas myeloid cells contribute to the immunosuppressive effects in anti-PD-1 therapies for NSCLCs with rare-driver mutations.