Translational lung cancer research最新文献

Anti-cancer T cells exhibit a spectrum of functional abilities and exhaustion levels and can be broadly categorized as stem-like exhausted T cells (Tex^stem) that retain cancer-killing capacity, and terminally exhausted T cells (Tex^term) with limited function. Previously, we identified CD8 Tex^stem and Tex^term cells in malignant pleural effusions (PEs) of non-small cell lung cancer (NSCLC) and mesothelioma patients. In both cancers, increased frequency of Tex^stem cells was associated with improved overall survival (OS). However, not all cancer patients develop PE, and sampling of PE is invasive, with associated risks. In this study we sought to determine if Tex^stem and Tex^term cells in the blood of patients with NSCLC also associated with survival. Using flow cytometry, we quantified Tex^stem and Tex^term in blood samples from 30 patients with advanced NSCLC and assessed their correlation with OS. In half of these cases, we also analyzed matched PE samples for comparison. Compared to PE, peripheral blood had a lower frequency of Tex^stem (3.8% vs. 9.4% of CD8 T cells, P=0.006) and Tex^term (0.3% vs. 1.1%, P=0.002). However, both subsets were significantly correlated between the two sites (Tex^stem r=0.82, P<0.001; Tex^term r=0.63, P=0.01). Higher Tex^stem cell frequency in the blood was associated with improved survival after adjusting for potentially prognostic patient and tumor related factors. When stratified into high and low groups based on the median, higher Tex^stem cells levels correlated with better OS [hazard ratio (HR) 0.16, 95% confidence interval (CI): 0.03-0.10, P=0.048]. As shown previously in PE, Tex^term cells in the blood did not correlate with OS. Our results further support the importance of Tex^stem in the anti-cancer immune response and provide useful evidence for the utility of peripheral blood sampling for future studies examining exhausted T cells (Tex).

Background: Glucose transporter 1 (GLUT1) is a transmembrane protein responsible for the transportation of glucose across the cell membrane that is often overexpressed in cancer. Due to a key role in cancer glucose metabolism and its membranous localization GLUT1 represents a potential therapeutic target. Our study was designed to elucidate the prevalence of GLUT1 expression and potential associations with tumor phenotype as well as patient outcome in different lung cancer subtypes.

Methods: A tissue microarray containing 858 resected lung cancers was analyzed for GLUT1 expression by immunohistochemistry.

Results: GLUT1 staining was significantly more prevalent and intense in squamous cell carcinoma (SCC, 97.3%) than in pulmonary adenocarcinoma (AC, 62.9%; P<0.001). Of the 225 SCCs, GLUT1 staining was observed in 219 (97.3%) tumors and considered strong in 75.6%, moderate in 15.1%, and weak in 6.7%. In 439 ACs, GLUT1 staining was seen in 276 (62.9%) tumors and considered strong in 14.6%, moderate in 16.4% and weak in 31.9%. High GLUT1 staining was significantly linked to advanced pT stage (P=0.03), nodal metastasis (P<0.001), high grade (P<0.001) and poor overall survival (OS) (P=0.01) in ACs. In SCCs, high GLUT1 staining was unrelated to pT, pN, and histologic grade but significantly linked to OS (P=0.03).

Conclusions: It is concluded that GLUT1 expression is commonly expressed in lung cancer and that a high level of expression is linked to unfavorable tumor features and/or poor prognosis in both AC and SCC.

Background: Guidelines for driver-negative, resectable stage IIA-IIIB non-small cell lung cancer (NSCLC) recommend surgery combined with neoadjuvant chemotherapy and perioperative immunotherapy. However, the relative efficacy and surgery-related safety comparing various immune checkpoint inhibitors (ICIs) remain unclear. This study aims to directly compare the efficacy and surgery-related safety of perioperative tislelizumab versus pembrolizumab in this setting.

Methods: In this single-institution retrospective cohort study, we enrolled patients with stage IIA-IIIB NSCLC who received neoadjuvant chemotherapy combined with either tislelizumab or pembrolizumab, followed by surgery and adjuvant immunotherapy at our center (2018-2024). Propensity score matching (PSM) was used to balance baseline characteristics. The primary endpoint was pathologic complete response (pCR). Secondary endpoints included major pathologic response (MPR), objective response rate (ORR), overall survival (OS), event-free survival (EFS), and surgery-related safety.

Results: In total, 245 patients were analyzed (75 in the tislelizumab group and 170 in the pembrolizumab group). Following a 1:1 PSM adjustment, each group consisted of 72 patients. No significant differences between tislelizumab group and pembrolizumab group were observed in terms of the pCR rate (43.1% vs. 40.3%; P=0.74), MPR rate (66.8% vs. 66.8%; P>0.99) or ORR (58.3% vs. 66.7%; P=0.30). There were no statistically significant differences between the tislelizumab group and pembrolizumab group in the endpoints of overall OS [hazard ratio (HR) =1.43, 95% confidence interval (CI): 0.59-3.48, P=0.42] and EFS (HR =1.93, 95% CI: 0.96-3.85, P=0.059). There was no significant difference regarding to the surgery-related safety outcomes, including operative time (160.97 vs. 177.80 min, P=0.12), intraoperative blood loss (195.95 vs. 239.73 mL, P=0.28), postoperative chest tube duration (6.594 vs. 7.656 days, P=0.15), and postoperative hospital days (10.00 vs. 10.77 days, P=0.32).

Conclusions: Tislelizumab and pembrolizumab demonstrated comparable drug efficacy and surgery-related safety among patients with resectable stage IIA-IIIB NSCLC undergoing neoadjuvant chemoimmunotherapy.

Background and objective: Pulmonary sarcomatoid carcinoma (PSC) accounts for approximately 0.5% of non-small cell lung cancer (NSCLC) cases and is thus a rare subtype. Highly aggressive and hard to detect early, PSC responds poorly to surgery, radiotherapy, and chemotherapy. Therefore, this review aims to synthesize current evidence on its pathogenesis and emerging therapeutic strategies, to improve clinical management.

Methods: We searched PubMed for original studies, reviews, clinical trials, and case reports on PSC published until 2025. Moreover, data from ClinicalTrials.gov and major academic conference proceedings were examined for inclusion in this narrative review.

Key content and findings: The core pathophysiology of PSC is epithelial-mesenchymal transition (EMT), a process that drives biphasic differentiation of tumor cells and remodels the tumor microenvironment (TME), thereby promoting high invasiveness and treatment resistance. Therapeutically, although targetable mutations such as MET exon 14 skipping are relatively frequent in PSC, the efficacy of targeted agents is generally inferior to that for other NSCLC subtypes. Notably, the tumor immune microenvironment of PSC features significant immune cell infiltration and high programmed death-ligand 1 (PD-L1) expression, leading to a generally better response to immune checkpoint inhibitors (ICIs). Consequently, immunotherapy combined with chemotherapy or antiangiogenic agents has emerged as a productive therapeutic strategy.

Conclusions: Precision therapy for PSC, particularly immunotherapy-based combination strategies, has demonstrated transformative potential. However, further efforts in this field should involve clarifying the relevant EMT and tumor heterogeneity mechanisms, optimizing existing treatment regimens, and conducting targeted clinical trials, as these measures may advance individualized precision therapy for patients with PSC and improve their outcomes.

Background: Brain metastases (BMs) from non-small cell lung cancer (NSCLC) remain a major clinical challenge, and existing prognostic tools such as the Graded Prognostic Assessment (GPA) do not incorporate imaging biomarkers or adequately reflect the impact of immunotherapy. Meningeal lymphatic vessels (mLVs), which regulate cerebrospinal fluid drainage and immune surveillance, have been implicated in tumor-immune interactions. We aimed to develop and internally validate a multivariable prognostic model integrating mLV remodeling measured by black-blood magnetic resonance imaging (BB-MRI) with clinical predictors to improve early prediction of treatment response.

Methods: We retrospectively analyzed 130 patients with pathologically confirmed NSCLC (100 with BM, 30 without BM). Among the BM cohort, 56 patients achieved favorable treatment response [stable disease (SD) or partial response (PR)] and 44 experienced progressive disease (PD). Candidate predictors were pre-specified based on clinical relevance, and the final model incorporated total mLV diameter, immunotherapy exposure, sex, and extracranial lesion count. Internal validation was performed with 1,000 bootstrap resamples. Model performance was assessed by discrimination, calibration, and decision curve analysis (DCA).

Results: The final multivariable model demonstrated good discrimination [area under the curve (AUC) =0.82; 95% confidence interval (CI): 0.75-0.90], excellent calibration, and consistent net clinical benefit across a range of threshold probabilities. The calibration and decision curves showed promising internal performance, but external validation is required before clinical application.

Conclusions: BB-MRI-derived mLV remodeling may be an early and noninvasive indicator of treatment efficacy in BM. The proposed nomogram enables the individualized prediction of systemic therapy response, supporting precision immunotherapy for patients with intracranial metastases.

Background: SMARCA4-deficient non-small cell lung cancer (SD-NSCLC) is a highly aggressive malignancy with a poor prognosis, and the clinical efficacy of immune checkpoint inhibitors (ICIs) in this context remains under investigation. This study focuses on patients with SD-NSCLC, investigating the efficacy of ICIs and the risk factors affecting prognosis, while also conducting a preliminary exploration of the underlying mechanisms through The Cancer Genome Atlas (TCGA) database.

Methods: From October 2020 to May 2025, 95 patients with SD-NSCLC, confirmed by immunohistochemistry (IHC) at Tianjin Medical University Cancer Institute & Hospital, were included for analysis. Validation and molecular mechanism exploration were conducted using the TCGA database. Disease-free survival (DFS) and progression-free survival (PFS) were the primary endpoints of the study. The disease control rate (DCR) was a secondary endpoint.

Results: In stage IV SD-NSCLC patients, no significant difference in PFS was observed between those treated with ICIs and non-ICIs (P=0.60). However, the median PFS (mPFS) differences were significant between STK11/KEAP1 mutant-type (mut) and wild-type (wt) groups (1.0 vs. 6.5 months, P=0.007). Even after ICI treatment, the difference in mPFS between the STK11/KEAP1 wt and mut groups remained significant (P=0.02). Additionally, there was a significant difference in the mPFS between the SD group treated with ICIs and the non-SD group (6.0 vs. 11.0 months, P=0.003). TCGA analysis revealed that SMARCA4 loss-of-function (LOF) mutations had significantly shorter mPFS compared to non-LOF mutations (18.66 vs. 57.56 months, P=0.02). Differential gene expression and enrichment analysis, along with immune infiltration analysis, revealed that SMARCA4-LOF was associated with gene silencing and immune suppression, which may explain the limited efficacy of ICIs.

Conclusions: SMARCA4 deficiency is an independent prognostic factor for NSCLC, as validated using the TCGA database. Co-mutations with STK11/KEAP1 further exacerbate poor prognosis, suggesting that specific gene co-mutations may influence treatment response and survival. Moreover, SMARCA4 deficiency leads to poor responses to immunotherapy, potentially due to core metabolic disorders, inactivation of tumor suppressor signaling, and immune suppression in the tumor microenvironment. These findings suggest that treatment strategies should be adjusted to address these molecular mechanisms.

Background: Anaplastic lymphoma kinase (ALK) rearrangement is a key driver mutation in lung adenocarcinoma (LUAD). Despite its established role in advanced diseases, the prognostic impact of ALK rearrangement on early-stage LUAD remains unexplored. Therefore, we aimed to explore the prognostic value of ALK rearrangement in surgically treated stage I LUAD by analyzing patient demographics, tumor characteristics, recurrence, and therapy patterns.

Methods: This retrospective study reviewed postoperative pathologic stage I LUAD patients who underwent ALK rearrangement testing at West China Hospital, Sichuan University. The prognostic impact of ALK rearrangement on recurrence-free survival (RFS), along with clinicopathologic features, mutational profiles, and targeted therapy patterns of ALK-positive patients, was assessed.

Results: The cohort comprised 3,775 patients, of whom 165 (4.37%) were ALK-positive. ALK rearrangement rates were significantly higher in females (P=0.048), stage IB (P<0.001), and those without epidermal growth factor receptor (EGFR) mutations (P<0.001). ALK-positive tumors were more likely to exhibit high-risk radio-pathological features for recurrence, with the trend being more pronounced in stage IA cases. ALK-positive patients showed worse RFS compared to negative ones (log-rank P=0.009), but this difference did not remain significant in multivariable analysis [hazard ratio (HR) =1.72; P=0.09]. Further analysis revealed that ALK rearrangement was significantly associated with an increased risk of metastasis [odds ratio (OR) =2.15; P=0.045], particularly to the bone (OR =5.38; P<0.001) and brain (OR =2.88; P=0.041) after adjusting for confounders.

Conclusions: ALK rearrangements were linked to more aggressive histology and increased risk of bone and brain metastases in resected, stage I LUADs, emphasizing the potential relevance of molecular profiling in postoperative risk assessment and treatment planning, even in stage IA patients.

Background and objective: The increasing use of neoadjuvant therapy in non-small cell lung cancer (NSCLC) has magnified the importance of pathologic response as a treatment endpoint. However, there are persistent challenges in its assessment and interpretation. This review aimed to synthesize current methods and challenges in evaluating pathologic response in patients with NSCLC, summarize available assessment techniques and biomarkers, and collate current data on pathologic response to neoadjuvant treatments and the association with survival outcomes.

Methods: We selected and reviewed articles proposing guidelines or approaches to the pathologic assessment of NSCLC, articles describing challenges in assessing pathologic response in NSCLC, and studies reporting pathologic response to neoadjuvant treatment and/or the association between pathologic response and survival outcomes. Data were extracted and summarized descriptively.

Key content and findings: In this review, we summarize methods for evaluating pathologic response in patients with resectable NSCLC and highlight current challenges, including variability in pathologic response assessment, the limited standardization of techniques and biomarkers, and the difficulty of interpreting pathologic response. We also review current clinical data on pathologic response to neoadjuvant chemotherapy, radiotherapy, immunotherapy, tyrosine kinase inhibitors (TKIs), and antiangiogenic therapies, and the association between pathologic response and survival outcomes. Finally, we review and discuss the selection of optimal treatment strategies for patients who achieve a pathologic response to neoadjuvant therapy.

Conclusions: Pathologic response is a valuable indicator of early response to treatment, but its current limitations necessitate a cautious and balanced approach in treatment decision-making for patients with early-stage resectable NSCLC, with consideration also given to other factors such as long-term survival and quality of life.

Background: The mesenchymal-epithelial transition factor (MET) gene is a key therapeutic target in non-small cell lung cancer (NSCLC), affecting the tumor expression of programmed cell death ligand 1 (PD-L1) and the immune microenvironment. This study examined the relationship between cellular MET (c-MET) expression, immune profiles, and survival in patients with NSCLC treated with radiochemotherapy and consolidative immunotherapy.

Methods: c-MET expression levels and immune profiles, including cluster of differentiation 8 (CD8), cluster of differentiation 68 (CD68), lymphocyte-activation gene 3 (LAG3), forkhead box protein P3 (FOXP3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), were accessed in 60 locally advanced patients with NSCLC treated with radiochemotherapy and sequential immunotherapy at Shanghai Pulmonary Hospital. Correlations between c-MET gene expression and immune cell infiltration were additionally explored using publicly available transcriptomic datasets and bioinformatics analysis. Categorical data were analyzed with Chi-squared tests, survival functions were derived from Kaplan-Meier estimates, and Cox regression assessed the independent impact on overall survival (OS) and progression-free survival (PFS).

Results: PFS and OS for the cohort were 24.0 and 34.0 months, respectively. OS was significantly associated with reduced macrophage (CD68⁺) infiltration (P=0.03), while PFS was significantly associated with high c-MET expression (P=0.03). Correlation analysis indicated a significant correlation between c-MET expression and macrophage (CD68⁺) infiltration (P=0.01).

Conclusions: c-MET expression and macrophage (CD68⁺) infiltration were identified as potential predictors of survival and were found to be significantly correlated with one another. These findings suggest that antibody-drug conjugates targeting c-MET in combination with immune checkpoint inhibitors may represent a potentially effective consolidation therapy strategy following chemoradiotherapy in patients with locally advanced NSCLC.