Translational lung cancer research最新文献

Background: The effectiveness of different immune checkpoint inhibitors (ICIs) (i.e., pembrolizumab or sintilimab) in combination with chemotherapy in the treatment of resectable non-small cell lung cancer (NSCLC) is unknown. Using propensity score matching (PSM), this study aimed to analyze the preliminary results of using neoadjuvant chemotherapy in combination with sintilimab or pembrolizumab in the treatment resectable NSCLC.

Methods: NSCLC patients who received neoadjuvant pembrolizumab or sintilimab in combination with chemotherapy at two hospitals between June 2018 and March 2024 were recruited for the study. PSM was used to analyze the differences between the two groups in terms of the objective response rate (ORR), pathological complete response (pCR) rate, and operation-related information.

Results: A total of 366 patients were enrolled in the study: 163 in the sintilimab group (SG) and 203 in the pembrolizumab group (PG). Of the patients, 159 (43.4%) achieved a pCR, of whom 70 (42.9%) and 89 (43.8%) belonged to the SG and PG, respectively (P=0.86). No significant differences were observed between the SG and PG in terms of the major pathological response (MPR) rate (108, 66.3% vs. 127, 62.5%, P=0.46) and ORR (116, 71.2% vs. 126, 62.1%, P=0.07). The logistic analyses indicated that treatment with ≥3 cycles of neoadjuvant treatment and squamous cell cancer remained significant promoting factors of pCR. After PSM, the pCR rate and ORR were also similar between the SG and PG (63 of 140, 45.0% vs. 63 of 140, 45.0%, P>0.99; 93 of 140, 66.4% vs. 82 of 140, 58.6%, 17.1%). The 1- and 3-year overall survival (OS) rates of the PG were 98.7% and 79.3%, while those of the SG were 98.1% and 75.6% (P=0.73). After PSM, the 1- and 3-year OS rates of the PG were 95.3% and 77.0%, while those of the SG were 98.8% and 79.4%, respectively (P=0.22).

Conclusions: The combination of sintilimab or pembrolizumab with chemotherapy demonstrated similar effectiveness in terms of achieving a pCR in the neoadjuvant treatment of resectable NSCLC, and yielded comparable treatment outcomes.

Background and objective: Lung cancer remains the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis and therapy resistance. Despite advances in targeted therapies and immunotherapies, the prognosis remains poor. There is a critical need for minimally invasive biomarkers that enable early detection, prognostic stratification and therapeutic monitoring. Exosomes, a subtype of extracellular vesicles, have emerged as promising candidates in this context given their role in intercellular communication and their selective cargo, which reflects the molecular state of tumor cells. This review aims to summarize the current evidence on the potential of exosomes and their cargo, particularly microRNAs (miRNAs), as diagnostic and prognostic biomarkers as well as therapeutic tools in lung cancer.

Methods: A comprehensive literature search was conducted using PubMed/MEDLINE and Scopus databases between January 3 and April 30, 2025. Studies published from January 2000 to April 2024 were included if they addressed the role of exosomes in lung cancer diagnosis, prognosis, or therapy. Two reviewers independently screened titles and abstracts and full texts were assessed based on predefined inclusion criteria. Relevant articles were also identified through reference lists.

Key content and findings: Exosomal miRNAs (microRNAs) have shown potential as biomarkers for early detection, disease subtype classification, prognosis and therapy resistance in lung cancer. Multiple studies have identified specific miRNA signatures associated with tumor burden, histological subtypes and clinical outcomes. Exosomes also contribute actively to oncogenesis through promoting angiogenesis, epithelial-mesenchymal transition, immune evasion and drug resistance. Furthermore, exosomes are being investigated both as therapeutic targets and delivery systems due to their ability to transfer functional biomolecules selectively and safely. Despite these advances, challenges remain regarding standardization of isolation methods, heterogeneity in miRNA signatures and clinical validation.

Conclusions: Exosomes represent a dynamic and promising platform for improving the diagnosis, prognosis and treatment of lung cancer. Although technical and translational hurdles remain, their integration into clinical practice may enhance personalized and precision oncology strategies. Continued research and technological advancements are necessary to fully unlock their potential in routine cancer care.

Background: There is a significant unmet clinical need for accurate target identification in diagnosis and treatment of malignant tumors, including lung cancer. Optical imaging, specifically fluorescence-based, enables real-time tracking during endoscopic or surgical procedures. Here, we aim to investigate the scenario in which the fluorescence signal is possibly not due to the presence of the administered fluorescent agent, using a preclinical transbronchial lung cancer model.

Methods: Pafolacianine is a folate analog conjugated with an indocyanine green-like dye (peak excitation 774-776 nm, detection 794-796 nm). A composite optical fiberscope (COF) with 0.97 mm outer diameter tip was used for laser excitation at 776 nm and imaging. Spectrometer measurements along the same optical axis as the COF were also made to characterize the signal. In a mouse xenograft model, human folate receptor-positive KB tumor cells were inoculated subcutaneously into the flank of immunodeficient (NCr-Foxn1^nu) mice and grown to 8-15 mm diameter. The mice were then infused with 0.025 or 0.25 mg/kg pafolacianine or negative control. At 24 hours after infusion, tumor and contralateral background spectral measurements were acquired using both the COF imaging system and the spectrometer. In a swine peribronchial model, a pafolacianine-infused tumor was placed manually on the outer wall of the swine bronchus by forceps. The COF was inserted into the working channel of a bronchoscope, which was then inserted through an endotracheal tube and navigated close to where the tumor was located. While changing the distance from the COF tip to the bronchial mucosa, transbronchial COF imaging and spectroscopic measurements were acquired separately.

Results: In the in vivo mouse xenograft model, we observed a peak in the spectrometer spectrum at 810 nm that was more intense in the 0.25 mg/kg cohort than in the 0.025 mg/kg pafolacianine cohort. In the swine peribronchial tumor model with negative control tumor, we observed the excitation laser signal (776 nm) with the spectrometer when the COF tip was placed in very close (~1 mm) proximity to the bronchial mucosa but this signal was not detected at 5 or 10 mm distance.

Conclusions: In situations of very close proximity of the COF to the bronchial wall (~1 mm), we detected both excitation and emission signals. When the distance was increased slightly, only the fluorescence emission signal was detected. Although these results are not fully generalizable to all fluorescence bronchoscopy settings, it is important for clinicians to be aware of possible limitations in the filter rejection of excitation light leakage and to avoid extreme proximity between the bronchial mucosa and the fiber tip. We report this to exemplify artefacts that can occur in fluorescence bronchoscopy.

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.