bims-meluca 2024-11-24 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–11–24
ten papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Association between higher glucose levels and reduced survival in patients with non-small cell lung cancer treated with immune checkpoint inhibitors.
Obesity-Specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin.
Comprehensive serum biomarker analysis reveals IL-8 changes as the only predictor of the effectiveness of immune checkpoint inhibitors for patients with advanced non-small cell lung cancer.
The association between metabolic syndrome and lung cancer risk: a Mendelian randomization study.
Prediction of the Survival Status, Immunotherapy Response, and Medication of Lung Adenocarcinoma Patients Based on Hypoxia- and Apoptosis-Related Genes.
Clinical impact of preoperative sarcopenia and immunonutritional impairment on postoperative outcomes in non-small cell lung cancer surgery.
Total baseline tumor size predicts survival among patients with advanced small-cell lung cancer receiving chemotherapy plus programmed death-ligand 1 inhibitor as first-line therapy: a multicenter retrospective observational study.
Correlation of hemoglobin, albumin, lymphocyte, and platelet score with prognosis in patients with stage III squamous lung cancer.
Gut metatranscriptomics based de novo assembly reveals microbial signatures predicting immunotherapy outcomes in non-small cell lung cancer.
Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.

Lung Cancer. 2024 Nov 15. pii: S0169-5002(24)00557-9. [Epub ahead of print]198 108023

Association between higher glucose levels and reduced survival in patients with non-small cell lung cancer treated with immune checkpoint inhibitors.

Soravis Osataphan, Muhammad Awidi, Yu Jen Jan, Krishna Gunturu, Shriram Sundararaman, Hollis Viray, Edward Frankenberger, Melissa Mariano, Lauren O'Loughlin, Andrew Piper-Vallillo, Katherine Stafford, Aleksandra Kolnick, Hind Ghazalah, Kartik Sehgal, Mary-Elizabeth Patti, Daniel Costa, Prudence Lam, Deepa Rangachari.

   BACKGROUND: Obesity and hypercholesterolemia have been associated with better responses to ICIs in NSCLC, while type 2 diabetes (T2D) has been associated with a worse response. However, the association between glucose levels and outcomes remains unknown. This study investigated the impact of mean baseline glucose levels, T2D, dyslipidemia, and obesity on overall survival (OS) in NSCLC patients undergoing ICI therapy.
METHODS: A multicenter retrospective cohort study was conducted using data from three medical centers, with locally advanced or metastatic NSCLC patients receiving ICI, regardless of treatment line or concurrent therapy. Random venous glucose levels within 4 weeks prior to ICI initiation, BMI, history of dyslipidemia, and T2D, along with OS, were assessed. Patients with BMI < 18.5 were excluded.
RESULTS: Among 438 patients, those with the highest quartile of baseline glucose levels had significantly shorter OS compared to those in the lowest quartile (HR, 1.53; 95 % CI, 1.08 - 2.15; p-value = 0.016). This association remind consistent after adjusting for steroid use, diabetes, performance status and glucose-lowering medication use. These effects were consistently observed in subsets of patients treated with ICI monotherapy and with PD-L1 TPS ≥ 1 %.
CONCLUSION: Higher mean baseline glucose levels correlated with shorter survival in patients with NSCLC treated with ICIs. The divergent effects of individual metabolic syndrome components on ICI response in patients with NSCLC underscore the complexity of metabolic influences on treatment outcomes.

Keywords:  Dyslipidemia; Glucose; Immune Checkpoint Inhibitors; Metabolic Syndrome; Metabolically Healthy Obesity; Non-Small-Cell Lung Cancer; Type 2 Diabetes

DOI:  https://doi.org/10.1016/j.lungcan.2024.108023
J Natl Cancer Inst. 2024 Nov 19. pii: djae295. [Epub ahead of print]

Obesity-Specific improvement of lung cancer outcomes and immunotherapy efficacy with metformin.

Randall J Smith, Robert Zollo, Sukumar Kalvapudi, Yeshwanth Vedire, Akhil Goud Pachimatla, Cara Petrucci, Garrison Shaller, Deschana Washington, Vethanayagam Rr, Stephanie N Sass, Aravind Srinivasan, Eric Kannisto, Sawyer Bawek, Prantesh Jain, Spencer Rosario, Joseph Barbi, Sai Yendamuri.

BACKGROUND: Pre-clinical cancer studies ascribe promising anticancer properties to metformin. Yet, clinical findings vary, casting uncertainty on its therapeutic value for non-small cell lung cancer (NSCLC) patients. We hypothesized that metformin could benefit obese and overweight patients with NSCLC.
METHODS: We retrospectively analyzed two clinical cohorts and employed complementary mouse models to test our hypothesis. One cohort included NSCLC patients with overweight BMI (≥25, n = 511) and non-overweight BMI (<25, n = 232) who underwent lobectomy, evaluating metformin's impact on clinical outcomes. Another cohort examined metformin's effect on progression-free survival (PFS) after immune checkpoint inhibitors (ICI) in overweight (n = 284) vs non-overweight (n = 184) NSCLC patients. Metformin's effects on tumor progression, antitumor immunity, and ICI response in obese and normal-weight mice were assessed with lung cancer models.
RESULTS: Metformin is associated with increased recurrence-free survival in overweight patients (HR = 0.47 [95%CI = 0.24-0.94], p = .035) after lobectomy. It also corrected accelerated tumor growth in diet-induced obese mouse models in a lymphocyte-specific manner while reversing several mechanisms of immune suppression potentiated by obesity. PD-1 blockade coupled with metformin was more effective at limiting tumor burden in obese mice and correlated with PFS only in overweight patients on immunotherapy (HR = 0.60, [95%CI = 0.39-0.93], p = .024).
CONCLUSIONS: Metformin may improve lung cancer-specific clinical outcomes in obese and overweight lung cancer patients and enhance immunotherapy efficacy in this growing population as well. This work identifies obesity as a potential predictive biomarker of metformin's anticancer and immunotherapy-enhancing properties in lung cancer while shedding light on the underlying immunological phenomena.

DOI: https://doi.org/10.1093/jnci/djae295
Lung Cancer. 2024 Nov 09. pii: S0169-5002(24)00551-8. [Epub ahead of print]198 108017

Comprehensive serum biomarker analysis reveals IL-8 changes as the only predictor of the effectiveness of immune checkpoint inhibitors for patients with advanced non-small cell lung cancer.

Hiroaki Akamatsu, Yasuhiro Koh, Makoto Nishio, Yasushi Goto, Hidetoshi Hayashi, Satoru Miura, Koji Tamada, Hiroshi Kagamu, Akihiko Gemma, Ichiro Yoshino, Toshihiro Misumi, Atsuto Mouri, Ryota Saito, Naoto Takase, Noriko Yanagitani, Hiroshi Nokihara, Masahiro Seike, Kei Takamura, Masahide Mori, Shunichiro Iwasawa, Shintaro Nakagawa, Tetsuya Mitsudomi.

   OBJECTIVES: Programmed cell death ligand 1 (PD-L1) expression is widely used to predict the effectiveness of PD-(L)1 inhibitors despite its imperfection. Previous studies suggested the utilization of various serum biomarkers; nonetheless, findings are inconclusive because of limited sample sizes or the focus on a single biomarker in many of these studies. This study analyzed multiplex serum biomarkers to explore their predictive ability in a large cohort of patients with advanced non-small-cell lung cancer (NSCLC) treated with a PD-L1 inhibitor in a real-world setting.
MATERIALS AND METHODS: This was a sub-study of J-TAIL, a prospective observational study of atezolizumab monotherapy in pre-treated patients with advanced NSCLC. From April to October 2019, 262 patients were enrolled from 73 sites in Japan. Serum samples were collected at baseline and at the second dose of atezolizumab. Quantification of the 51 serum cytokines, chemokines, growth factors, and vascular endothelial growth factors was performed using the Luminex platform. Baseline values and fold changes of the time of the second dose to the baseline were examined in association with the effectiveness of atezolizumab.
RESULTS: Among the 51 proteins assessed, a higher baseline interleukin (IL)-12 level, a higher soluble CD40 ligand fold change, a lower IL-8 fold change were associated with higher objective response rate (ORR). Of these, only the lower IL-8 fold change was associated with better progression-free survival (PFS) (adjusted hazard ratio, 1.98; 95 % confidence interval, 1.45-2.70; P < 0.01). Multivariate analysis demonstrated that the lower IL-8 fold change was an independent factor for both the ORR and PFS. The IL-8 fold change was independent of the neutrophil/lymphocyte ratio, and durable PFS was observed in patients with both low.
CONCLUSION: Comprehensive serum biomarker analysis revealed that a lower fold change in serum IL-8 was associated with better outcomes in pre-treated patients with advanced NSCLC receiving atezolizumab.

Keywords:  Atezolizumab; Chemokine; Cytokine; Immune checkpoint inhibitor; Interleukin-8; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.lungcan.2024.108017
Sci Rep. 2024 11 18. 14(1): 28494

The association between metabolic syndrome and lung cancer risk: a Mendelian randomization study.

Zhicheng Wei, Yunyun Hu, Fang Zuo, Xiushu Wen, Desheng Wu, Xiaodong Sun, Conghai Liu.

Metabolic syndrome (MetS) is closely linked to cancer development, with emerging evidence suggesting its association with pulmonary carcinoma. However, causal relationships remain unclear due to observational study limitations. Employing Mendelian randomization, we investigated the causal link between MetS and lung cancer (LC) susceptibility. The data utilized in this study were obtained from the publicly available genetic variation summary database. The causal relationship was assessed using the inverse variance weighting method (IVW), weighted median method, and MR-Egger regression. A sensitivity analysis was carried out to confirm the robustness of the findings. Furthermore, risk factor analyses were conducted to explore potential mediators. Utilizing various analyses, MetS demonstrated a significant positive association with LC (OR, 1.22; 95% CI, 1.09-1.37, p = 7.57 × 10- 4), lung squamous cell carcinoma (LUSC) (OR, 1.47; 95%, 1.23-1.75, p = 2.22 × 10- 5), and small cell lung cancer (SCLC) (OR, 1.76; 95% CI, 1.37-2.26, p = 8.20 × 10- 6) but not lung adenocarcinoma (LUAD) (OR, 1.08; 95% CI, 0.94-1.24, p = 0.28). Risk factor analyses indicated that smoking, alcohol, body mass index, education, and type 2 diabetes might mediate the association. This study genetically validates and reinforces the evidence of MetS increasing the incidence of LC, including both LUSC) and SCLC, especially among individuals with abdominal obesity. It provides valuable insights for the development of lung cancer prevention strategies and directions for future research.

DOI: https://doi.org/10.1038/s41598-024-79260-y
Horm Metab Res. 2024 Nov 22.

Prediction of the Survival Status, Immunotherapy Response, and Medication of Lung Adenocarcinoma Patients Based on Hypoxia- and Apoptosis-Related Genes.

Ziliang Shi, Zi Sang, Junmeng Xiao, Jianbin Hou, Mingfei Geng.

To predict patient survival prognosis, we aimed to establish a novel set of gene features associated with hypoxia and apoptosis. RNA-seq and clinical data of LUAD were sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, while hypoxia and apoptosis-related genes were obtained from the Molecular Signatures Database (MsigDB). A 13-gene-prognostic model incorporating hypoxia and apoptosis genes was developed using univariate/multivariate Cox regression, Nonnegative Matrix Factorization (NMF) clustering, and LASSO regression. Patients were divided into high-risk (HR) and low-risk (LR) groups according to the median risk score. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed distinct biological processes between HR and LR groups, including hormone regulation and lipid metabolism pathways. Single sample gene set enrichment analysis (ssGSEA) indicated elevated cell infiltration levels of Neutrophils and T_helper_cells in the LR group, while NK cells and Th1cells were higher in the HR group. Immunophenoscore (IPS) and tumor immune dysfunction and exclusion (TIDE) analyses suggested potential benefits of immunotherapy for LR group patients. In conclusion, this prognostic feature integrating hypoxia- and apoptosis-related genes offers insights into predicting survival, immune status, and treatment response in LUAD patients, paving the way for personalized treatment strategies.

DOI: https://doi.org/10.1055/a-2458-7088
Lung Cancer. 2024 Nov 01. pii: S0169-5002(24)00538-5. [Epub ahead of print]198 108004

Clinical impact of preoperative sarcopenia and immunonutritional impairment on postoperative outcomes in non-small cell lung cancer surgery.

Atsuki Uchibori, Satoru Okada, Masanori Shimomura, Tatsuo Furuya, Chiaki Nakazono, Tomoki Nishimura, Masayoshi Inoue.

   OBJECTIVES: This study aimed to clarify the relationship between preoperative sarcopenia and prognostic nutritional index (PNI) statuses and clinicopathological factors in patients with non-small cell lung cancer (NSCLC) who underwent surgical resection, and to evaluate short- and long-term outcomes by stratifying groups according to sarcopenia and PNI status as prognostic predictors.
MATERIALS AND METHODS: This study included 300 patients with p-Stage I-IIIA NSCLC who underwent complete resection with lobectomy. Sarcopenia was assessed using the skeletal muscle index (SMI) and the immunonutritional index was evaluated using the PNI. The first quartile was used as the cutoff for the sarcopenia/non-sarcopenia and low/high-PNI groups.
RESULTS: The median patient age was 70 years, and 184 patients (61.3 %) were male individuals. The median PNI was 50.2, and the median SMI was 48.1 and 37.5 for male and female patients, respectively. The median follow-up period was 64 months (60 patients died). Survival analysis showed that overall survival was significantly worse in the sarcopenia and low-PNI groups than in the control group (p = 0.002 and p < 0.001, respectively). When stratified by sarcopenia and PNI status, the sarcopenia with low-PNI group had a particularly poor prognosis (5-year survival rate, 52.8 % [p < 0.001]). Multivariable Cox regression analysis revealed that sarcopenia with low PNI was an independent prognostic factor that indicated a poor outcome. The response to drug treatment for postoperative recurrence was significantly worse in the sarcopenia with low-PNI group than inthe other group.
CONCLUSION: The combination of preoperative sarcopenia and immunonutritional impairment had a negative clinical impact independent of tumor factors, and patients with these two indications had a particularly poor prognosis. These factors may be associated with poor responses to drug treatment for postoperative recurrence. The evaluation of skeletal muscle mass using preoperative imaging and nutritional assessment using serum markers may be useful for perioperative management and prognosis prediction.

Keywords:  Non-small cell lung cancer; Prognosis; Prognostic nutritional index; Sarcopenia; Skeletal muscle index; Surgery

DOI:  https://doi.org/10.1016/j.lungcan.2024.108004
Front Oncol. 2024 ;14 1400277

Total baseline tumor size predicts survival among patients with advanced small-cell lung cancer receiving chemotherapy plus programmed death-ligand 1 inhibitor as first-line therapy: a multicenter retrospective observational study.

Anna Tanaka, Shuhei Teranishi, Yukihito Kajita, Tomofumi Hirose, Ayami Kaneko, Yu Sairenji, Hidetoshi Kawashima, Kentaro Yumoto, Toshinori Tsukahara, Kenji Miura, Nobuaki Kobayashi, Masaki Yamamoto, Ryuichi Nishihira, Makoto Kudo, Naoki Miyazawa, Masanori Nishikawa, Takeshi Kaneko.

   Introduction: Total baseline tumor size (BTS) is a prognostic factor for programmed death 1 and programmed death-ligand 1 (PD-L1) inhibitor treatments. However, the prognostic value of total BTS for patients with small-cell lung cancer (SCLC) who receive chemotherapy plus PD-L1 inhibitor remains unknown. Thus, in this study, we aimed to determine whether total BTS is associated with prognosis in patients with SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.
Methods: This study included patients with extensive-stage SCLC or post-chemoradiotherapy recurrence of limited-stage SCLC who received chemotherapy plus PD-L1 inhibitor as first-line therapy from August 2019 to December 2022. The two lesions with the largest diameter among the measurable lesions in each organ were selected from up to five organs (maximum of 10 lesions), and the sum of all diameters was defined as total BTS. The patients were divided into two groups, large or small, with total BTS using X-tile software. Median survival was analyzed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Univariate and multivariate analyses examined the association between total BTS and prognosis.
Results: Fifty patients were included; 14% had large total BTS (>183.2 mm) and 86% had small total BTS (≤183.2 mm). The median observation period was 10.5 months. The large total BTS group showed significantly worse overall survival than the small total BTS group (median: 26.8 months vs. 5.7 months, P = 0.0003). The multivariate analysis indicated that large total BTS was an independent negative predictor of overall survival (hazard ratio: 7.14, 95% confidence interval: 1.89-26.96).
Discussion: Total BTS is a potentially useful prognostic factor for patients with advanced SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.

Keywords:  baseline tumor size; first-line therapy; immune checkpoint inhibitor; overall survival; programmed death-ligand 1 inhibitor; small-cell lung cancer

DOI:  https://doi.org/10.3389/fonc.2024.1400277
J Thorac Dis. 2024 Oct 31. 16(10): 7016-7028

Correlation of hemoglobin, albumin, lymphocyte, and platelet score with prognosis in patients with stage III squamous lung cancer.

Jing-Chen Huo, Yue Wang, Jing-Wei Su, Sui Liu, Atsushi Osoegawa, Zhong-Fei Jia, Yu-Xiang Wang, Jie Yang.

   Background: Among cancers, lung cancer has the second highest incidence rate and the highest mortality rate in the world. Identifying suitable biomarkers to assist in the prognostic prediction of lung cancer is crucial for developing individualized treatment plans. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score has been applied to predict patient prognosis across a variety of cancers. This study aimed to investigate the predictive value of the HALP score for the prognosis of patients with stage III squamous cell lung cancer.
Methods: The clinical data of patients with stage III squamous lung cancer who had undergone radical radiotherapy at the Department of Radiotherapy of The Fourth Hospital of Hebei Medical University from January 2011 to December 2020 were retrospectively analyzed. The optimal cutoff values for continuous variables were determined using X-Tile software. A Cox proportional hazards model was used for univariate and multivariate analysis, the Kaplan-Meier method was used for survival analysis, and log-rank test was used to check for differences.
Results: A total of 206 patients were included in this study, and the cutoff value for the HALP score was 24.3. There were statistically significant differences between the high- and low-HALP-score groups in terms of alcohol consumption history, tumor-node-metastasis (TNM) stage, prognostic nutritional index (PNI) score, and systemic immune-inflammation index (SII) score. The median overall survival (OS) was 11.0 and 22.0 months in the low- and high-HALP-score groups, respectively (P<0.001), and the median progression-free survival (PFS) was 8.0 and 13.0 months, respectively (P=0.002). Univariate analysis showed that a low HALP score was significantly associated with OS [hazard ratio (HR) =1.698, 95% confidence interval (CI): 1.261-2.286; P<0.001] and PFS (HR =1.584, 95% CI: 1.176-2.132; P=0.002) in patients with stage III lung squamous carcinoma, while the multivariate analysis showed that a low HALP score was the most important factor in OS (HR =1.538, 95% CI: 1.137-2.079; P=0.005) and PFS (HR =1.399, 95% CI: 1.033-1.895; P=0.03) as independent predictors of poor prognosis.
Conclusions: In patients with stage III squamous cell lung cancer treated with radical radiotherapy, low baseline HALP score is associated with its poorer OS and PFS and may thus be valuable prognostic factor.

Keywords:  Hemoglobin; albumin; lung squamous carcinoma; lymphocyte and platelet; prognosis

DOI:  https://doi.org/10.21037/jtd-24-1513
J Transl Med. 2024 Nov 19. 22(1): 1044

Gut metatranscriptomics based de novo assembly reveals microbial signatures predicting immunotherapy outcomes in non-small cell lung cancer.

David Dora, Peter Kiraly, Csenge Somodi, Balazs Ligeti, Edit Dulka, Gabriella Galffy, Zoltan Lohinai.

   BACKGROUND: Advanced-stage non-small cell lung cancer (NSCLC) poses treatment challenges, with immune checkpoint inhibitors (ICIs) as the main therapy. Emerging evidence suggests the gut microbiome significantly influences ICI efficacy. This study explores the link between the gut microbiome and ICI outcomes in NSCLC patients, using metatranscriptomic (MTR) signatures.
METHODS: We utilized a de novo assembly-based MTR analysis on fecal samples from 29 NSCLC patients undergoing ICI therapy, segmented according to progression-free survival (PFS) into long (> 6 months) and short (≤ 6 months) PFS groups. Through RNA sequencing, we employed the Trinity pipeline for assembly, MMSeqs2 for taxonomic classification, DESeq2 for differential expression (DE) analysis. We constructed Random Forest (RF), Support Vector Machine (SVM), and Extreme Gradient Boosting (XGBoost) machine learning (ML) algorithms and comprehensive microbial profiles.
RESULTS: We detected no significant differences concerning alpha-diversity, but we revealed a biologically relevant separation between the two patient groups in beta-diversity. Actinomycetota was significantly overrepresented in patients with short PFS (vs long PFS, 36.7% vs. 5.4%, p < 0.001), as was Euryarchaeota (1.3% vs. 0.002%, p = 0.009), while Bacillota showed higher prevalence in the long PFS group (66.2% vs. 42.3%, p = 0.007), when comparing the abundance of corresponding RNA reads. Among the 120 significant DEGs identified, cluster analysis clearly separated a large set of genes more active in patients with short PFS and a smaller set of genes more active in long PFS patients. Protein Domain Families (PFAMs) were analyzed to identify pathways enriched in patient groups. Pathways related to DNA synthesis and Translesion were more enriched in short PFS patients, while metabolism-related pathways were more enriched in long PFS patients. E. coli-derived PFAMs dominated in patients with long PFS. RF, SVM and XGBoost ML models all confirmed the predictive power of our selected RNA-based microbial signature, with ROC AUCs all greater than 0.84. Multivariate Cox regression tested with clinical confounders PD-L1 expression and chemotherapy history underscored the influence of n = 6 key RNA biomarkers on PFS.
CONCLUSION: According to ML models specific gut microbiome MTR signatures' associate with ICI treated NSCLC outcomes. Specific gene clusters and taxa MTR gene expression might differentiate long vs short PFS.

Keywords:  De novo assembly; Gut microbiome; Immune-checkpoint inhibitor; Immunotherapy; Machine learning; Metatranscriptome; Progression-free survival

DOI:  https://doi.org/10.1186/s12967-024-05835-y
bioRxiv. 2024 Oct 28. pii: 2024.10.23.619897. [Epub ahead of print]

Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung cancer.

Shayna Thomas-Jardin, Shruthy Suresh, Ariana Arce, Nicole Novaresi, Emily Stein, Lisa Thomas, Cheryl Lewis, Chul Ahn, Bret M Evers, Maria E Salvatierra, Wei Lui, Khaja Khan, Luisa Maris Solis Soto, Ignacio Wistuba, John D Minna, Kathryn A O'Donnell.

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces Programmed Death Ligand 1 (PD-L1), leading to suppression of anti-tumor immunity. Here we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. We show that CD155 and PD-L1 are coordinately induced by the ISR, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames (uORFs) in their 5' UTRs. Analysis of primary human lung tumors identifies a significant correlation between PD-L1 and CD155 expression. ISR activation accelerates tumorigenesis and inhibits T cell function, effects that can be overcome by combining PD-1 blockade with the ISR inhibitor ISRIB. These studies uncover a novel mechanism by which two immune checkpoint proteins are coordinately regulated and suggest a new therapeutic strategy for lung cancer patients.
Statement of Significance: This study uncovers a novel mechanism for the coordinated translational regulation of the PD-L1/PD1 and CD155/TIGIT immune checkpoint pathways and highlights the ISR as a therapeutic vulnerability for lung cancer. Inhibition of the ISR pathway bolsters PD-1 blockade, potentially unveiling a new therapeutic strategy for lung cancer patients.

DOI: https://doi.org/10.1101/2024.10.23.619897