bims-meluca 2025-02-09 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–02–09
seventeen papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer.
Multiparameter body composition analysis on chest CT predicts clinical outcomes in resectable non-small cell lung cancer.
Targeting HVEM-GPT2 axis: a novel approach to T cell activation and metabolic reprogramming in non-small cell lung cancer therapy.
Construction of a lung adenocarcinoma prognostic model based on KEAP1/NRF2/HO‑1 mutation‑mediated upregulated genes and bioinformatic analysis.
Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma.
Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells.
Efficacy of first-line chemotherapy combined with immunotherapy or anti-angiogenic therapy in advanced KRAS-mutant non-small cell lung cancer.
PRMT5 Inhibition Enhances Therapeutic Efficacy of Cisplatin via Mediating miR-29b-3p-Mcl-1 Expression in Lung Adenocarcinoma.
GUK1 activation is a metabolic liability in lung cancer.
The effect of baseline versus early glucocorticoid use on immune checkpoint inhibitor efficacy in patients with advanced NSCLC.
Broadening horizons: research on ferroptosis in lung cancer and its potential therapeutic targets.
IL-10RA promotes lung cancer cell proliferation by increasing fatty acid oxidation via STAT3 signaling pathway.
Spatially mapping the tumour immune microenvironments of non-small cell lung cancer.
High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models.
O-GlcNAcylation attenuates ischemia-reperfusion-induced pulmonary epithelial cell ferroptosis via the Nrf2/G6PDH pathway.
CD34 evaluation of microvasculature in lung adenocarcinoma and its microvascular density predicts postoperative tumor recurrence.
The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling.

Life Sci. 2025 Feb 04. pii: S0024-3205(25)00077-3. [Epub ahead of print] 123444

CRBN deletion enhances mitochondrial metabolism by stimulating mitochondrial calcium accumulation in non-small cell lung cancer.

Seungheon Shin, Steve K Cho.

  CRBN (Cereblon), a substrate receptor of the CRL4 (Cullin4-RING E3 ubiquitin ligase) complex, has emerged as a key player in cancer metabolism. While its role in influencing metabolic phenotypes has been suggested, the precise functions of CRBN in cellular metabolism and cancer progression remain underexplored. This study investigates the impact of CRBN downregulation in lung cancer, focusing on mitochondrial metabolism and cellular functions. Data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) revealed significant reductions in CRBN expression at both mRNA and protein levels in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This downregulation was further confirmed in most lung cancer cell lines examined. Functional analyses of CRBN knockout (KO) cells revealed substantial alterations in mitochondrial metabolism, including enhanced oxidative phosphorylation, increased mitochondrial membrane potential (ΔΨm), and elevated production of mitochondrial reactive oxygen species (mROS). CRBN deficiency also accelerated tricarboxylic acid (TCA) cycle flux and increased mitochondrial calcium accumulation, contributing to elevated ΔΨm and potentially compromised mitochondrial integrity. Additionally, CRBN KO cells demonstrated increased cell migration, which could be mitigated by inhibiting mitochondrial calcium import. These findings suggest that CRBN plays a pivotal role in regulating mitochondrial function and metabolic activity in non-small cell lung cancer. The loss of CRBN enhances mitochondrial metabolism and contributes to increased cancer cell migration, providing new insights into the metabolic adaptations associated with CRBN deficiency in cancer progression.

Keywords:  Cereblon; Lung cancer; Mitochondrial activity; Mitochondrial calcium accumulation

DOI:  https://doi.org/10.1016/j.lfs.2025.123444
Insights Imaging. 2025 Feb 06. 16(1): 32

Multiparameter body composition analysis on chest CT predicts clinical outcomes in resectable non-small cell lung cancer.

Yilong Huang, Hanxue Cun, Zhanglin Mou, Zhonghang Yu, Chunmei Du, Lan Luo, Yuanming Jiang, Yancui Zhu, Zhenguang Zhang, Xin Chen, Bo He, Zaiyi Liu.

   OBJECTIVES: This study investigates the association between baseline CT body composition parameters and clinical outcomes in patients with resectable non-small cell lung cancer (NSCLC).
METHODS: Patients who underwent surgical resection for NSCLC between January 2006 and December 2017 were retrospectively enrolled in this multicenter study. Body composition metrics, including the area of skeletal muscle, intermuscular adipose tissue, subcutaneous adipose tissue, visceral adipose tissue, muscle radiodensity, and derivative parameters from five basic metrics mentioned before, were calculated based on preoperative non-contrast-enhanced chest CT images at L1 level. The Cox proportional hazards regression analysis was used to evaluate the association between body composition metrics and survival outcomes including overall survival (OS) and disease-free survival (DFS).
RESULTS: A total of 2712 patients (mean age, 61.53 years; 1146 females) were evaluated. A total of 635 patients (23.41%) died. 465 patients (19.51%) experienced recurrence and/or distant metastasis. After multivariable adjustment, skeletal muscle index (SMI, HR = 0.86), intermuscular adipose index (IMAI, HR = 1.49), and subcutaneous adipose index (SAI, HR = 0.96) were associated with OS. Similar results were found after stratification by gender, TNM stage, and center. There was no significant association between all body composition metrics and DFS (all p > 0.05). The body composition metrics significantly enhance the model including clinicopathological factors, resulting in an improved AUC for predicting 1-year and 3-year OS, with AUC values of 0.707 and 0.733, respectively.
CONCLUSIONS: SMI, IMAI, and SAI body composition metrics have been identified as independent prognostic factors and may indicate mortality risk for resectable NSCLC patients.
CRITICAL RELEVANCE STATEMENT: Our findings emphasize the significance of muscle mass, quality, and fat energy storage in clinical decision-making for patients with non-small cell lung cancer (NSCLC). Nutritional and exercise interventions targeting muscle quality and energy storage could be considered for patients with NSCLC.
KEY POINTS: Multiparameter body composition analysis is associated with the clinical outcome in NSCLC patients. Assessing muscle mass, quality, and adipose tissue helps predict overall survival in NSCLC. The quantity and distribution of body composition can contribute to unraveling the adiposity paradox.

Keywords:  Body composition; Computed tomography; Disease-free survival; Lung cancer; Overall survival

DOI:  https://doi.org/10.1186/s13244-025-01910-0
Cancer Immunol Immunother. 2025 Feb 04. 74(3): 101

Targeting HVEM-GPT2 axis: a novel approach to T cell activation and metabolic reprogramming in non-small cell lung cancer therapy.

Yuanshan Yao, Chunji Chen, Bin Li, Wen Gao.

   BACKGROUND: The modulation of tumor microenvironments through immune checkpoint pathways is pivotal for the development of effective cancer immunotherapies. This study aims to explore the role of HVEM in non-small cell lung cancer (NSCLC) microenvironment.
METHODS: The lung cancer datasets for this study were directly downloaded from The Cancer Genome Atlas (TCGA). Single-cell data were sourced from the Tumor Immune Single-cell Hub (TISCH). Multiplex immunohistochemistry (mIHC) was used to explore the cellular composition and spatial distribution of HVEM in lung cancer immune microenvironment. The immune microenvironment of HVEM KO mice bearing mouse lung cancer cell was also evaluated. Co-cultured system and phenotype assays facilitated the examination of Jurkat T cells' effect on A549 and H1299 lung cancer cells. Quantitative PCR and Western blotting determined gene and protein expression, respectively, cellular respiration was measured through oxygen consumption rate (OCR) assays. Lung cancer cells co-cultured with Jurkat T cells were xenografted into nude mice to evaluate tumor growth and metastatic potential. Next, RNA-seq, COIP, Dual-luciferase reporter experiment, and CHIP-seq were used to explore the potential underlying mechanism.
RESULTS: In our study, we investigated the role of HVEM in the microenvironment of NSCLC and its implications in immunotherapy. Crucially, HVEM, part of the tumor necrosis factor receptor superfamily, influences T cell activation, potentially impacting immunotherapeutic outcomes. Using the TIDE algorithm, our results showcased a link between HVEM levels and immune dysfunction in NSCLC patients. Delving deeper into the NSCLC microenvironment, we found HVEM predominantly expressed in T cell subpopulations. CD8 + HVEM + and CD4 + HVEM + indicated better prognosis in lung adenocarcinoma tissue microarray using multiplex immunohistochemistry. Activated T cells, particularly from the Jurkat cell line, significantly inhibited NSCLC progression, reducing both proliferation and invasion capabilities of A549 and H1299 lung cancer cell lines. In vivo models reinforced these observations. Manipulating HVEM expression revealed its essential role in T cell survival and activation. In addition, animal experiments revealed the importance of HVEM in maintaining activated peripheral immunity and inflamed local tumor microenvironment. Furthermore, our data suggest that HVEM is pivotal in T cell metabolic reprogramming, transitioning from oxidative phosphorylation to aerobic glycolysis. RNA sequencing illuminated a potential relationship between HVEM and GPT2, an enzyme tied to amino acid metabolism and cellular energetics. Subsequent experiments confirmed that HVEM's influence on T cell activation and metabolism is potentially mediated through its regulation of GPT2. In addition, GATA1 was validated to regulate HVEM expression in activated Jurkat T cells.
CONCLUSIONS: Our study establishes that HVEM significantly influences T cell functionality and NSCLC cell dynamics, pinpointing the HVEM-GPT2 axis as a promising target for NSCLC therapy.

Keywords:  HVEM; Immunotherapy; Jurkat cells; NSCLC

DOI:  https://doi.org/10.1007/s00262-025-03949-w
Oncol Lett. 2025 Mar;29(3): 155

Construction of a lung adenocarcinoma prognostic model based on KEAP1/NRF2/HO‑1 mutation‑mediated upregulated genes and bioinformatic analysis.

Wei Zhu, Ye Zhang, Lingyun Yang, Lu Chen, Chaobo Chen, Qifeng Shi, Zipeng Xu.

  Lung adenocarcinoma (LUAD) is a prevalent malignant tumor of the respiratory tract. The Kelch like ECH associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) axis serves a pivotal role in the occurrence and progression of LUAD. The present study aimed to identify specific genes regulated by mutations of the KEAP1/NRF2/HO-1 axis and to investigate their prognostic potential in LUAD, as well as their association with the tumor microenvironment. Immunohistochemistry was performed to assess the expression levels of KEAP1, NRF2 and HO-1 in LUAD tissues and to evaluate their association with clinical pathology. Sequencing data and clinical information were obtained from The Cancer Genome Atlas (TCGA)-LUAD and Gene Expression Omnibus (GSE68465) databases, whilst mutation information was sourced from the cBio Cancer Genomics Portal website. The R package 'limma' and Venn diagram were utilized to identify upregulated differentially expressed genes. Subsequently, a prognostic model was constructed using univariate Cox regression analysis and 101 machine learning methods. A nomogram of the prognostic model was generated to assess its efficacy in evaluating survival among patients with LUAD. The 'ImmuCellAI' and 'oncoPredict' R packages were used to compare and evaluate differences in immune cell infiltration and immunotherapy between high- and low-risk groups, as well as the sensitivity of LUAD to chemotherapy drugs. Compared with the group with negative expression, the results revealed that the group with positive expression of NRF2 and HO-1 exhibited advanced tumor, lymph node and clinical stages and a worse prognosis. A predictive model incorporating four genes (kynureninase, serpin family B member 5, insulin like 4 and γ-aminobutyric acid type A receptor subunit α3) was constructed based on KEAP1/NRF2/HO-1 mutation-mediated upregulated genes (KNHMUGs). Risk score was an independent prognostic factor for patients with LUAD (hazard ratio, 1.038; 95% confidence interval, 1.034-1.043; P<0.001). A nomogram was developed to predict the prognosis of patients with LUAD, which was validated as a reliable prognostic tool. The low-risk group exhibited higher immune cell infiltration, including CD4+ T, CD8+ T, natural killer (NK) and NKT cells, compared with the high-risk group. In addition, it demonstrated increased expression levels of immune checkpoint inhibitory genes such as cytotoxic T-lymphocyte associated protein 4, T cell immunoreceptor with Ig and ITIM domains, hepatitis A virus cellular receptor 2 and B and T lymphocyte associated protein. Moreover, it displayed enhanced sensitivity to immunotherapy. Drug sensitivity analysis revealed that the high-risk group exhibited increased sensitivity towards vinblastine, docetaxel and cisplatin, whereas the low-risk group showed increased sensitivity to BMS_754807, SB505124_1194 and JQ1_2172. In conclusion, a KNHMUGs-based gene signature was constructed in the present study, which holds promise as a biomarker for evaluating patient prognosis and guiding treatment by effectively assessing immunotherapy response and chemotherapy sensitivity in patients with LUAD.

Keywords:  Kelch like ECH associated protein 1/nuclear factor erythroid 2-related factor 2/heme oxygenase 1; drug prediction; immunotherapy; lung adenocarcinoma; mutation; prognostic model; tumor immune microenvironment

DOI:  https://doi.org/10.3892/ol.2025.14902
Biol Direct. 2025 Feb 07. 20(1): 19

Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma.

Ruilan Ma, Dian Yang, Peng Wang, Ziyi Zhang, Xuehong Zhang, Jialiang Song, Han Liu, Shuyan Liu, Yingqiu Zhang, Lijuan Zou.

  Members from the RAS GTPase superfamily have been closely implicated in the tumorigenesis of various human cancers. Recent sequencing analysis of lung adenocarcinoma has revealed the prevalence of alterations in the RIT1 gene that is a close RAS paralog. However, relative to RAS subfamily members KRAS, NRAS, and HRAS, our characterization of RIT1 oncogenic properties remains incomplete. Therefore, further investigation on RIT1 will facilitate future development of targeted therapies. Our bioinformatic analysis revealed that RIT1 alterations in lung cancer predicted poor survivals but differed from its RAS paralogs by showing largely amplification and mutation. Through biochemical characterization of RIT1 hotspot mutations, we propose that RIT1 alterations were associated with increased protein abundance that promoted cell growth. Transcriptomic profiling indicated that oncogenic RIT1 mutant expression influenced common tumorigenic RAS/MAPK, PI3K/AKT, and E2F1 pathways, in addition to altered NFE2L2 target expression. Importantly, RIT1 mutants markedly sensitized cells to ferroptosis induction, and RIT1 knockdown suppressed ferroptotic cell death. Lung adenocarcinoma NCI-H2110 cells containing endogenous RIT1 M90I mutation were susceptible to ferroptosis induction both in vitro and in vivo within xenograft models. Hence, our study unravels a novel aspect of RIT1 mutations in lung cancer and suggests ferroptosis induction as a potential therapeutic strategy to treat lung cancer patients carrying RIT1 mutations.

Keywords:  Ferroptosis; GTPase; Lung adenocarcinoma; NRF2; Oncogenic mutation; RAS family; RIT1

DOI:  https://doi.org/10.1186/s13062-025-00613-2
Pharmacol Res. 2025 Feb 03. pii: S1043-6618(25)00068-4. [Epub ahead of print]213 107643

Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells.

Zhiwei Yuan, Taiyan Yu, Xu Wang, Kelin Meng, Tianlai Wang, Boyu Wang, Yu Xi, Congjian Wang, Chenxi Zeng, Shaojie Hu, Yitao Tian, Hui Xiong, Qi Wang, Wenbin Zou, Xue Wang, Yi Gao, Xiangning Fu, Lequn Li.

  Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.

Keywords:  Autophagy; Glutamine metabolism; IFN-γ signaling; Immunotherapy; Non-small cell lung cancer; V9302

DOI:  https://doi.org/10.1016/j.phrs.2025.107643
Transl Oncol. 2025 Feb 03. pii: S1936-5233(25)00048-8. [Epub ahead of print]53 102317

Efficacy of first-line chemotherapy combined with immunotherapy or anti-angiogenic therapy in advanced KRAS-mutant non-small cell lung cancer.

Huiping Qiang, Yue Wang, Yao Zhang, Jingwen Li, Lincheng Zhang, Huawei Du, Xuxinyi Ling, Shuhui Cao, Yan Zhou, Runbo Zhong, Hua Zhong.

   BACKGROUND: Approximately 30 % non-small cell lung cancer (NSCLC) patients carry KRAS mutations in western countries. First-line chemotherapy combined with immunotherapy has been the standard therapeutic regimen for KRAS-mutant NSCLC patients. This population could also benefit from chemotherapy combined with anti-angiogenic therapy. However, few studies has reported on head-to-head efficacy comparisons between these two treatment strategies.
METHODS: We selected stage IV KRAS-mutated NSCLC patients diagnosed from 2017 to 2022. Their clinical baseline characteristics, first-line treatment strategy, whether combined TP53 or STK11 mutation, PD-L1 expression level, etc. were evaluated. The correlation between these factors and progression-free survival (PFS) and overall survival (OS) were analyzed.
RESULTS: A total of 273 patients received first-line systematic therapy. The most common mutation was KRAS G12C (34.3 %). First-line chemotherapy combined with immunotherapy brought significant survival benefits (mPFS: 11.0 months vs. 4.0 months, P = 0.0003; mOS: 17.0 months vs. 9.0 months, P = 0.0002) compared with first-line chemotherapy combined with anti-angiogenic therapy. Among the 203 patients who received first-line chemotherapy combined with immunotherapy, PD-L1 positive NSCLC patients responded better than PD-L1 negative patients (mPFS: 11.0 months vs. 4.0 months, P = 0.0004; mOS: 21.0 months vs. 11.0 months, P = 0.0005). ECOG PS score of 0-1 (HR=0.201, P = 0.001) and first-line chemotherapy combined with immunotherapy (HR=0.333, P = 0.009) were independent predictors of OS.
CONCLUSIONS: Compared with first-line chemotherapy combined with anti-angiogenic therapy, first-line chemotherapy combined with immunotherapy has brought significant survival benefit to advanced KRAS mutant NSCLC patients, especially for PD-L1 positive patients.

Keywords:  Immune checkpoint inhibitor; KRAS mutation; Non-small cell lung cancer; PD-L1; TP53

DOI:  https://doi.org/10.1016/j.tranon.2025.102317
Cell Biol Int. 2025 Feb 01.

PRMT5 Inhibition Enhances Therapeutic Efficacy of Cisplatin via Mediating miR-29b-3p-Mcl-1 Expression in Lung Adenocarcinoma.

Haichao Li, Jiangjiang Fan, Weiwei Shen, Yong Zhang, Ximing Zhu, Pei Li, Zhongping Gu, Pengyu Jing.

  Cisplatin is one of the front-line therapeutic agents used to treat cancers, while drug resistance is a great obstacle to anti-tumor efficiency. Protein arginine methyltransferase 5 (PRMT5) has been identified as a promoter of tumorigenesis, motility, and invasion. Inhibiting PRMT5 reduced hypoxia-induced carboplatin resistance in lung adenocarcinoma (LUAD). However, the specific relationship between PRMT5 and cisplatin (CDDP) warrants further investigation. Our research revealed that PRMT5 inhibitor C9 enhanced CDDP chemosensitivity by suppressing proliferation and promoting apoptosis in LUAD cells. Through examining pro-apoptotic proteins regulated by PRMT5, we identified that Mcl-1 played a significant role in PRMT5-mediated CDDP chemosensitivity. Furthermore, PRMT5 regulated Mcl-1 expression through mediating miR-29b-3p. In vivo, our research presented that C9 increased CDDP chemosensitivity in LUAD xenografts. All in all, our data raised an interesting possibility that epigenetic reprogramming was associated with chemosensitivity. PRMT5 inhibitor C9 improved CDDP effectiveness in LUAD cells by inhibiting Mcl-1 expression via miR-29b-3p, thereby modulating cellular proliferation and apoptosis.

Keywords:  Mcl‐1; PRMT5; apoptosis; cisplatin chemosensitivity; lung adenocarcinoma

DOI:  https://doi.org/10.1002/cbin.12278
Cell. 2025 Jan 28. pii: S0092-8674(25)00093-5. [Epub ahead of print]

GUK1 activation is a metabolic liability in lung cancer.

Jaime L Schneider, Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon M Gassaway, Christian W Johnson, Nicole Jones, Zongyu Li, Christian P Joschko, Toshio Fujino, Joao A Paulo, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A Stopka, Liam Kelley, Andrew Do, Mari Mino-Kenudson, Lecia V Sequist, Jessica J Lin, Nathalie Y R Agar, Steven P Gygi, Kevin M Haigis, Aaron N Hata, Marcia C Haigis.

  Little is known about metabolic vulnerabilities in oncogene-driven lung cancer. Here, we perform a phosphoproteomic screen in anaplastic lymphoma kinase (ALK)-rearranged ("ALK+") patient-derived cell lines and identify guanylate kinase 1 (GUK1), a guanosine diphosphate (GDP)-synthesizing enzyme, as a target of ALK signaling in lung cancer. We demonstrate that ALK binds to and phosphorylates GUK1 at tyrosine 74 (Y74), resulting in increased GDP biosynthesis. Spatial imaging of ALK+ patient tumor specimens shows enhanced phosphorylation of GUK1 that significantly correlates with guanine nucleotides in situ. Abrogation of GUK1 phosphorylation reduces intracellular GDP and guanosine triphosphate (GTP) pools and decreases mitogen-activated protein kinase (MAPK) signaling and Ras-GTP loading. A GUK1 variant that cannot be phosphorylated (Y74F) decreases tumor proliferation in vitro and in vivo. Beyond ALK, other oncogenic fusion proteins in lung cancer also regulate GUK1 phosphorylation. These studies may pave the way for the development of new therapeutic approaches by exploiting metabolic dependencies in oncogene-driven lung cancers.

Keywords:  ALK; GDP; GUK1; Ras signaling; anaplastic lymphoma kinase; cancer metabolism; guanylate kinase 1; lung cancer; non-small cell lung cancer; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.cell.2025.01.024
Front Oncol. 2025 ;15 1533556

The effect of baseline versus early glucocorticoid use on immune checkpoint inhibitor efficacy in patients with advanced NSCLC.

Yifan Wang, Jianying Zhou, Simin Peng, Zhao Cui, Weiqi Wang, Wenqin Zeng, Tingting Qiu, Zhentian Liu.

   Purpose: This study aims to investigate the specific effects of glucocorticoids (GC) on the efficacy of immune checkpoint inhibitors (ICIs), and whether this effect is influenced by the timing and dosage of GC administration. Changes in the neutrophil percentage and the helper/suppressor T lymphocyte ratio [NEUT %/(CD4+/CD8+)] during GC administration were monitored.
Methods: The clinical results of 130 patients with advanced non-small cell lung cancer (NSCLC) treated with ICIs were analyzed and compared with those of patients who did not use GC. Cox proportional hazards regression model and Logistic regression analysis were used to analyze the factors affecting ORR and PFS, and t test was used to analyze the changes of NEUT %/(CD4 +/CD8 +) during GC use.
Results: Multivariate Logistic analysis showed that GC use was associated with a higher ORR in 130 patients treated with ICIs [HR = 3.07,95% CI (1.31-7.21), P = 0.010]. Univariate Cox analysis showed that GC use was not significantly correlated with PFS [HR = 0.926,95% CI (0.603-1.420), P = 0.710]. Patients who used GC during the baseline period of ICIs treatment had a higher ORR than those who used GC at the early stage of ICIs treatment (65.4% vs 30.8%, p = 0.024). Multivariate Cox analysis showed that GC use had longer PFS [HR = 0.37,95% CI (0.17-0.78), p = 0.009]. The timing of GC use was different, and there was a difference in NEUT %/(CD4 +/CD8 +) levels before and after treatment. There was no significant difference in ORR and PFS between GC duration and dose.
Conclusion: The use of GC helps to enhance the efficacy of immunotherapy. In particular, GC use during the baseline period leads to higher ORR and PFS, regardless of the dose or duration of GC use. The levels of NEUT %/(CD4+/CD8+) varied depending on the timing of GC administration.

Keywords:  NEUT%/(CD4+/CD8+); efficacy; glucocorticoids; immune checkpoint inhibitors; non-small cell lung cancer; timing of use

DOI:  https://doi.org/10.3389/fonc.2025.1533556
Front Immunol. 2025 ;16 1542844

Broadening horizons: research on ferroptosis in lung cancer and its potential therapeutic targets.

Guangpeng Gao, Xindi Zhang.

  Ferroptosis is a novel form of cell death distinct from traditional mechanisms, characterized by the accumulation of iron ions and the production of lipid peroxides. It not only affects the survival of tumor cells but is also closely linked to changes in the tumor microenvironment. Lung cancer is one of the leading malignancies worldwide in terms of incidence and mortality, and its complex biological mechanisms and resistance make treatment challenging. Recent studies have shown that ferroptosis plays a key role in the onset and progression of lung cancer, with its intricate regulatory mechanisms influencing tumor development and response to therapy. As research into ferroptosis deepens, related molecular pathways, such as glutamate metabolism, iron metabolism, and antioxidant defense, have been gradually revealed. However, in clinical practice, ferroptosis-based therapeutic strategies for lung cancer are still in their early stages. Challenges remain, including the incomplete understanding of the specific mechanisms of ferroptosis, insufficient research on related regulatory factors, and limited insight into the interactions within the tumor microenvironment. Therefore, effective modulation of ferroptosis to enhance lung cancer treatment remains an urgent issue. This review summarizes the biological mechanisms of ferroptosis, analyzes the regulatory factors of ferroptosis in lung cancer cells and their interaction with the tumor microenvironment, and further explores potential therapeutic strategies targeting ferroptosis. By synthesizing the latest research, this paper aims to provide new perspectives and directions for lung cancer treatment, with the goal of advancing clinical applications.

Keywords:  cell death mechanisms; ferroptosis; lung cancer; molecular pathways; therapeutic strategies; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1542844
Pulm Pharmacol Ther. 2025 Jan 29. pii: S1094-5539(25)00001-X. [Epub ahead of print] 102344

IL-10RA promotes lung cancer cell proliferation by increasing fatty acid oxidation via STAT3 signaling pathway.

Wei Du, Yuqing Ouyang, Xiaofan Feng, Chunyan Yu, Haoke Zhang, Siqi Chen, Zixuan Liu, Bo Wang, Xueying Li, Zihe Liu, Weimin Deng.

  Metabolic reprogramming in tumor cells plays a crucial role in promoting cell proliferation and metastasis, and is currently recognized as a significant marker of tumor progression. Interleukin-10 receptor subunit alpha (IL-10RA), a member of the type II cytokine receptor family, is predominantly expressed on macrophages and T cells and plays a crucial role in regulating immune cell metabolism and immune response. However, its role in the energy metabolic pathways of tumor cells remains unclear. In this study, we found increased expression of IL-10RA in human non-small cell lung cancer (NSCLC), and a correlation between increased IL-10RA expression and tumor stage, tumor size, and short overall survival of patients with NSCLC. IL-10RA overexpression significantly promoted the proliferation of NSCLC cell lines and enhanced glycolysis and fatty acid oxidation (FAO), thereby boosting energy production. Correspondingly, the downregulation of IL-10RA inhibited proliferation, glycolysis, and FAO in NSCLC cell lines. Bioinformatic analyses indicated that IL-10RA upregulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. STAT3 inhibitor effectively blocked the increase in FAO levels and cell proliferation induced by IL-10RA overexpression. These findings suggest that IL-10RA accelerates NSCLC cell proliferation by increasing FAO levels via the STAT3 pathway, highlighting IL-10RA as a potential therapeutic target for NSCLC.

Keywords:  Energy metabolism; FAO; IL-10RA; NSCLC; STAT3 signaling pathway

DOI:  https://doi.org/10.1016/j.pupt.2025.102344
Nat Commun. 2025 Feb 04. 16(1): 1345

Spatially mapping the tumour immune microenvironments of non-small cell lung cancer.

Lysanne Desharnais, Mark Sorin, Morteza Rezanejad, Bridget Liu, Elham Karimi, Aline Atallah, Anikka M Swaby, Miranda W Yu, Samuel Doré, Saskia Hartner, Benoit Fiset, Yuhong Wei, Baharak Kadang, Roni Rayes, Philippe Joubert, Sophie Camilleri-Broët, Pierre-Olivier Fiset, Daniela F Quail, Jonathan D Spicer, Logan A Walsh.

Lung cancer is the leading cause of cancer-related deaths. An enhanced understanding of the immune microenvironments within these tumours may foster more precise and efficient treatment, particularly for immune-targeted therapies. The spatial architectural differences between lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are relatively unexplored. Here, we applied imaging mass cytometry to a balanced cohort of LUAD and LUSC patients, matched for clinical factors such as age, sex, and smoking history, to analyze 204 histopathology images of tumours from 102 individuals with non-small cell lung cancer (NSCLC). By analyzing interactions and broader cellular networks, we interrogate the tumour microenvironment to understand how immune cells are spatially organized in clinically matched adenocarcinoma and squamous cell carcinoma subsets. This spatial analysis revealed distinct patterns of immune cell aggregation, particularly among macrophage populations, that correlated with patient prognosis differentially in adenocarcinoma and squamous cell carcinoma, suggesting potential new strategies for therapeutic intervention. Our findings underscore the importance of analyzing NSCLC histological subtypes separately when investigating the spatial immune landscape, as microenvironmental characteristics and cellular interactions differed by subtype. Recognizing these distinctions is essential for designing precision therapies tailored to each subtype's unique immune architecture, ultimately enhancing patient outcomes.

DOI: https://doi.org/10.1038/s41467-025-56546-x
Front Immunol. 2024 ;15 1512605

High-dose ascorbic acid synergizes with anti-PD1 therapy in non-small cell lung cancer in vitro and in vivo models.

Hak Su Kim, Seung-Hyun Kwon, Ok Kyung Choi, Taekyu Lim.

   Introduction: Immune checkpoint inhibitors(ICIs) targeting programmed cell death protein 1 (PD1) confer significant survival benefits to patients with non-small cell lung cancer (NSCLC). However, there remains a substantial unmet need to identify therapeutic approaches to overcome resistance and provide benefits to these patients. High-dose ascorbic acid (AA) acts synergistically with many standard anticancer treatments. However, little is known about the effect of high-dose AA on improving the efficacy of anti-PD1 inhibitors in NSCLC. This study aimed to elucidate the effects of high-dose AA on anti-PD1 immunotherapy in NSCLC.
Methods: The combined effects of high-dose AA and anti-PD1 were investigated using a coculture model of H460 cells and CD8+ T cells and an LLC1 lung cancer syngeneic mouse model. To investigate the molecular mechanism, tumor tissues from mice were analyzed by comprehensive proteomic profiling using nano-LC-ESI-MS/MS.
Results: Pretreatment with a high dose of AA led to enhanced the sensitivity to the cytotoxicity of CD8+ T cells derived from healthy donor for H460 cells. Additionally, the combination of anti-PD1 and high-dose AA significantly increased CD8+ T cell cytotoxicity in H460 cells. The combination of anti-PD1 and high-dose AA showed dramatic antitumor effects in a syngeneic mouse model of lung cancer by significantly reducing tumor growth and increasing CD8+ T cell-dependent cytotoxicity and macrophage activity. Comprehensive protein analysis confirmed that high-dose AA in anti-PD1-treated tumor tissues enhanced the antitumor effects by regulating various immune-related mechanisms, including the B cell and T cell receptor signaling pathways, Fc gamma R-mediated phagocytosis, and natural killer (NK) cell-mediated cytotoxicity.
Discussion: Our results suggest that high-dose AA may be a promising adjuvant to potentiate the efficacy of anti-PD1 immunotherapy.

Keywords:  anti-PD1; high-dose ascorbic acid; immune checkpoint inhibitors; non-small cell lung cancer; proteomic analysis

DOI:  https://doi.org/10.3389/fimmu.2024.1512605
BMC Biol. 2025 Feb 04. 23(1): 32

O-GlcNAcylation attenuates ischemia-reperfusion-induced pulmonary epithelial cell ferroptosis via the Nrf2/G6PDH pathway.

Liuqing Yang, Hexiao Tang, Jin Wang, Dawei Xu, Rui Xuan, Songping Xie, Pengfei Xu, Xinyi Li.

   BACKGROUND: Lung ischemia-reperfusion (I/R) injury is a common clinical pathology associated with high mortality. The pathophysiology of lung I/R injury involves ferroptosis and elevated protein O-GlcNAcylation levels, while the effect of O-GlcNAcylation on lung I/R injury remains unclear. This research aimed to explore the effect of O-GlcNAcylation on reducing ferroptosis in pulmonary epithelial cells caused by I/R.
RESULTS: First, we identified O-GlcNAc transferase 1 (Ogt1) as a differentially expressed gene in lung epithelial cells of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, using single-cell sequencing, and Gene Ontology analysis (GO analysis) revealed the enrichment of the ferroptosis process. We found a time-dependent dynamic alteration in lung O-GlcNAcylation during I/R injury. Proteomics analysis identified the differentially expressed proteins enriched in ferroptosis and multiple redox-related pathways based on KEGG annotation. Thus, we generated Ogt1-conditional knockout mice and found that Ogt1 deficiency aggravated ferroptosis, as evidenced by lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), Fe2+, as well as alterations in critical protein expression glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Consistently, we found that elevated O-GlcNAcylation inhibited ferroptosis sensitivity in hypoxia/reoxygenation (H/R) injury-induced TC-1 cells via O-GlcNAcylated NF-E2-related factor-2 (Nrf2). Furthermore, both the chromatin immunoprecipitation (ChIP) assay and the dual-luciferase reporter assay indicated that Nrf2 could bind with translation start site (TSS) of glucose-6-phosphate dehydrogenase (G6PDH) and promote its transcriptional activity. As an important rate-limiting enzyme in the pentose phosphate pathway (PPP), elevated G6PDH provided a mass of nicotinamide adenine dinucleotide phosphate (NADPH) to improve the redox state of glutathione (GSH) and eventually led to ferroptosis resistance. Rescue experiments proved that Nrf2 knockdown or Nrf2-T334A (O-GlcNAcylation site) mutation abolished the protective effect of ferroptosis resistance.
CONCLUSIONS: In summary, we revealed that O-GlcNAcylation could protect against I/R lung injury by reducing ferroptosis sensitivity via the Nrf2/G6PDH pathway. Our work will provide a new basis for clinical therapeutic strategies for pulmonary ischemia-reperfusion-induced acute lung injury.

Keywords:  Ferroptosis; G6PDH; Lung ischemia–reperfusion; Nrf2; O-GlcNAcylation; Ogt1

DOI:  https://doi.org/10.1186/s12915-025-02126-w
Pathol Oncol Res. 2025 ;31 1611985

CD34 evaluation of microvasculature in lung adenocarcinoma and its microvascular density predicts postoperative tumor recurrence.

Zijian Qiu, Jiaji Wu, Guanchao Pang, Xia Xu, Jun Lin, Pingli Wang.

   Background: Angiogenesis is closely associated with tumor growth and metastasis, and microvascular density (MVD) is currently the clinical standard for evaluating tumor angiogenesis. Thus, the detection of intratumoral MVD is of great significance for understanding disease progression and predicting patient prognosis.
Methods: Tumor tissue sections of 238 patients with lung adenocarcinoma (LUAD) who underwent radical surgery were retrospectively analyzed. Immunohistochemical (IHC) staining was carried out using a CD34 polyclonal antibody to determine intratumoral MVD, and the relationship of CD34-MVD with the clinicopathological characteristics and survival time of LUAD patients was analyzed.
Results: CD34-MVD was associated with tumor size, lymph node metastasis, tumor recurrence, and patient survival status; patients with tumor size ≤3 cm (P = 0.015), negative for lymph node metastasis (P = 0.049), no tumor recurrence (P = 0.021), and survival (P = 0.042) had higher MVD. Survival analysis suggested that patients with high MVD had higher disease-free survival (log-rank P = 0.005) and overall survival (log-rank P = 0.004) compared to patients with low MVD. The Cox proportional hazards model showed that a high MVD (P = 0.022) reduced the risk of postoperative tumor recurrence in patients with LUAD.
Conclusion: Decreased intratumoral CD34 positive microvessels were associated with tumor development in patients with LUAD. CD34-MVD is an independent risk factor affecting postoperative tumor recurrence in patients with LUAD and can be used as a prognostic indicator for this group of patients.

Keywords:  CD34; lung adenocarcinoma; microvascular density; prognosis; tumor recurrence

DOI:  https://doi.org/10.3389/pore.2025.1611985
Commun Biol. 2025 Feb 04. 8(1): 178

The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling.

Yangyang Fu, Shishun Huang, Rulu Pan, Xingan Chen, Ting Liu, Rongzhe Zhang, Fangsheng Zhu, Qiwei Fang, Liyue Wu, Juji Dai, Ouchen Wang, Liting Lu, Xiduan Wei, Liangxing Wang, Xincheng Lu.

Phosphodiesterase 4D interacting protein (PDE4DIP) is a Golgi/centrosome-associated protein that plays critical roles in the regulation of microtubule dynamics and maintenance of the Golgi structure. However, its biological role in human cancer remains largely unknown. In this study, we showed that PDE4DIP is overexpressed in human non-small cell lung cancer (NSCLC) tissues and that upregulated PDE4DIP expression is associated with poor prognosis in patients with lung cancer. We demonstrated that PDE4DIP knockdown inhibits NSCLC cell proliferation in vitro and tumorigenicity in vivo. We further demonstrated that PDE4DIP knockdown triggers apoptosis and cell cycle arrest in NSCLC cells by activating the Protein kinase A (PKA) /CREB signalling pathway. PDE4DIP coordinates with A-kinase anchoring proteins 9 (AKAP9) to enhance the Golgi localization and stability of PKA RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα from the Golgi and leads to its degradation, thereby compromising its negative regulatory effect on PKA signalling. Overall, our findings provide novel insights into the roles of the PDE4DIP-AKAP9 complex in regulating PKA signalling and NSCLC growth and highlight PDE4DIP as a promising therapeutic target for NSCLC.

DOI: https://doi.org/10.1038/s42003-025-07621-y