bims-meluca 2026-04-26 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–04–26
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.
Lactylation-Mediated METTL14 Promotes Glycolysis Through Facilitating PGAM1 m6A Methylation in Non-Small Cell Lung Cancer.
Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.
NAT10 promotes lung cancer progression by enhancing glutamine metabolism through increasing ac4C modification on NIT2.
Immune-related gene expression profiling and alectinib efficacy for patients with ALK-Rearranged non-small cell lung cancer: exploratory analysis of a prospective observational study.
GFPT1 facilitates immune escape in lung adenocarcinoma by promoting the O-GlcNAcylation of MYC and regulating PD-L1.
10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.
Prognostic analysis and development of a prognostic model for EML4-ALK-positive lung cancer patients treated with ALK-TKIs.

Cancer Discov. 2026 Apr 20. OF1-OF20

LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.

Ray Pillai, Ali Rashidfarrokhi, Yuan Hao, Warren L Wu, Mariana C S Mancini, Burcu Karadal-Ferrena, Sofia G Dimitriadoy, Michael Cross, Anna H Yeaton, Shih Ming Huang, Arjun Bhutkar, Alberto M Herrera, Sahith Rajalingam, Makiko Hayashi, Kuan-Lin Huang, Eric Bartnicki, Anastasia-Maria Zavitsanou, Ellie Ivanova, Corrin Wohlhieter, Sarah E LeBoeuf, Ting Chen, Cynthia A Loomis, Ruth Kulicke, Fred P Davis, Nicolas Stransky, Gromoslaw Aleksander Smolen, Jun-Chieh J Tsay, Fernando Moreira Simabuco, Charles M Rudin, Andre L Moreira, Kamal M Khanna, Harvey I Pass, Kwok-Kin Wong, Shohei Koide, Aristotelis Tsirigos, Sergei B Koralov, Thales Papagiannakopoulos.

LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression.
SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0470
Immunol Invest. 2026 Apr 23. 1-19

Lactylation-Mediated METTL14 Promotes Glycolysis Through Facilitating PGAM1 m6A Methylation in Non-Small Cell Lung Cancer.

Qibin Wang, Guangjun Liu.

   OBJECTIVE: Non-small cell lung cancer (NSCLC) accounts for the highest proportion of lung cancers. METTL14 is a m6A methyltransferase affects the development of NSCLC. Lactylation can induced by glycolysis production lactate, but whether it modulates NSCLC through m6A methylation remains unclear. We aimed to determine whether METTL14 mediates NSCLC through glycolysis.
METHODS: METTL14 expression was validated in NSCLC clinical samples. Effects of METTL14 knockdown in NSCLC cells were evaluated by cell viability, colony formation and glycolysis. Lactylation was detceted by IP and western blotting.
RESULTS: We observed elevated METTL14 in NSCLC tissues and cells. METTL14 knockdown reduced cell viability, cell proliferation and glycolysis in NSCLC cells and tumor development in vivo. PGAM1 was the downstream target of METTL14, and METTL14 knockdown inhibited m6A level and mRNA stability of PGAM1. PGAM1 overexpression reversed the effect on METTL14 knockdown in NSCLC cells. Moreover, pan-lactylation, METTL14 expression and lactylation were upregulated in NSCLC tumor tissues, and exogenous promotion or inhibition of overall lactylation can promote or inhibit the lactylation level and protein stability of METTL14, respectively.
CONCLUSION: Lactylation enhanced METTL14 expression, thereby promoting PGAM1 m6A methylation to facilitate glycolysis in NSCLC. This finding uncovers a novel metabolic regulatory axis and offers a potential therapeutic target for NSCLC intervention.

Keywords:  Glycolysis; METTL14; PGAM1; lactylation; m6A; non-small cell lung cancer

DOI:  https://doi.org/10.1080/08820139.2026.2662683
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70295

Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.

Leng Han, Lingjie Jing, Xinting Zhu, Ciqin Li, Lu Bai, Yang Fang, Yuxuan Zhou, Dingyuan Bai, Jin Lu, Yonglong Han, Cheng Guo, Shumin Zhou, Quanjun Yang.

   BACKGROUND: Cancer cachexia is a debilitating syndrome characterized by severe skeletal muscle wasting, which significantly impairs patient quality of life and survival. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in tryptophan (Trp) metabolism, is often upregulated in cancers, but its specific role in driving lung cancer-associated cachexia remains inadequately defined. This study investigated the mechanistic role of Ido1 in cancer cachexia and evaluated the therapeutic potential of its inhibition.
METHODS: We established Lewis lung carcinoma (LLC) models in C57BL/6 mice using wild-type, Ido1-overexpressing (Ido1-OE) and Ido1-knockout (Ido1-KO) cells. Muscle mass, tumour growth and metabolic changes were assessed in vivo. Transcriptomic and targeted metabolomic analyses were performed on muscle and serum samples. In vitro, we examined the effects of tumour-conditioned media, the Trp metabolite kynurenine (Kyn) and Trp supplementation on C2C12 myotube atrophy. In vivo experiments verified the efficacy of the Ido1 inhibitor palmatine hydrochloride (PAL). Molecular pathways were analysed via western blot and qPCR.
RESULTS: Compared to LLC mouse models, Ido1-OE significantly exacerbated tumour growth and cachexia, leading to a significant decrease in lean body weight, gastrocnemius and tibialis anterior muscle weights (p < 0.01, p < 0.0001, p < 0.001). Gastrocnemius muscle fibre cross-sectional area significantly decreased in the Ido1-OE group (p < 0.0001). Transcriptomic analysis revealed that Ido1-OE activated pro-inflammatory and protein degradation pathways (upregulating MuRF1/Atrogin1, p < 0.05) while suppressing anabolic signalling pathways (oestrogen pathways, p < 0.01). Metabolomics analysis revealed unique metabolic signatures in Ido1-OE mice: Trp depletion and Kyn accumulation. In vitro experiments demonstrated that Ido1-OE enhanced LLC cell proliferation and migration capabilities (p < 0.0001, p < 0.0001). Tumour-conditioned medium (TCM) derived from Ido1-OE tumours significantly induced C2C12 myotube atrophy (p < 0.01). Similarly, direct treatment with Kyn led to dose-dependent muscle fibre shrinkage, with significant atrophy observed at 30 μM (p < 0.01) and 100 μM (p < 0.0001). Notably, the myotube atrophy induced by Kyn was significantly reversed by the addition of supplemental Trp (p < 0.0001). Compared with the Ido1-OE group, PAL treatment reduced gastrocnemius and tibialis anterior atrophy (p < 0.01; p < 0.05). Mechanistically, PAL inhibited the mRNA expression levels of MuRF1/Atrogin1 (p < 0.0001, p < 0.001), as well as their corresponding protein levels (p < 0.0001, p < 0.0001). Furthermore, PAL restored the phosphorylation level of mTOR (p < 0.001), as well as the mRNA expression of myosin heavy chain (p < 0.01).
CONCLUSIONS: Our findings demonstrate that Ido1 accelerates muscle atrophy and cancer cachexia by driving a metabolic reprogramming centred on the Trp-Kyn pathway. Pharmacological inhibition of Ido1 with PAL effectively mitigates these effects, positioning Ido1 as a promising therapeutic target for treating cancer cachexia.

Keywords:  cancer cachexia; indoleamine 2,3‐dioxygenase 1; kynurenine; metabolic reprogramming; muscle atrophy; tryptophan

DOI:  https://doi.org/10.1002/jcsm.70295
Mol Immunol. 2026 Apr 23. pii: S0161-5890(26)00088-X. [Epub ahead of print]194 104-113

NAT10 promotes lung cancer progression by enhancing glutamine metabolism through increasing ac4C modification on NIT2.

Dafu Yang, Yue Zhu, Yang Liu, Zhaoxia Dai.

  Glutamine metabolism plays a critical role in lung cancer progression due to its substantial contribution to energy supply. NAT10 is currently the only known ac4C transferase and regulates gene expression and mRNA stability through ac4C modification, thereby influencing tumor progression. This study aimed to investigate the mechanisms by which NAT10 mediates glutamine metabolism in lung cancer. The UALCAN database was used to perform pan-cancer analysis and assess NAT10 expression in lung cancer. Cell viability, proliferation, and migration were evaluated to characterize malignant behaviors in lung cancer cells. Glutamine metabolism was assessed by measuring glutamine consumption, as well as α-ketoglutarate (α-KG) and ATP production. NAT10-associated genes were identified from the GSE3141 dataset and subjected to pathway enrichment analysis. The underlying mechanism was explored using methylated RNA immunoprecipitation and dual-luciferase reporter assays. The role of NAT10 in lung cancer progression in vivo was assessed using a xenograft model. Results showed that NAT10 was upregulated in lung cancer cells and promoted cell viability, proliferation, migration, and glutamine metabolism in A549 and H460 cells, whereas NAT10 inhibition reversed these effects. Mechanistically, NAT10 enhanced ac4C modification of NIT2 and increased NIT2 mRNA stability. Overexpression of NIT2 restored cell viability, proliferation, migration, and glutamine metabolism that were suppressed by NAT10 knockdown in A549 and H460 cells. Furthermore, inhibition of NAT10 reduced tumor growth and glutamine metabolism in nude mice. Collectively, our findings demonstrate that NAT10 promotes glutamine metabolism in lung cancer by enhancing ac4C modification of NIT2, providing new insights into the mechanisms underlying lung cancer progression.

Keywords:  Ac4C; Glutamine metabolism; Lung cancer; NAT10; NIT2

DOI:  https://doi.org/10.1016/j.molimm.2026.04.010
Lung Cancer. 2026 Apr 19. pii: S0169-5002(26)00477-0. [Epub ahead of print]216 109416

Immune-related gene expression profiling and alectinib efficacy for patients with ALK-Rearranged non-small cell lung cancer: exploratory analysis of a prospective observational study.

Takashi Kurosaki, Shinichiro Suzuki, Yasutaka Watanabe, Hirotsugu Kenmotsu, Shoichi Itoh, Masafumi Yamaguchi, Ayako Shiono, Takuji Suzuki, Toshihide Yokoyama, Yukihiro Toi, Hisashi Tanaka, Masahide Oki, Takeshi Tsuda, Eiki Ichihara, Koichi Azuma, Hiroshi Tanaka, Ryo Arai, Ken Uchibori, Eisaku Miyauchi, Ryohei Katayama, Hidetoshi Hayashi.

   BACKGROUND: The development of resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and a poor response to immune checkpoint inhibitors (ICIs) remain challenges in ALK-rearranged non-small cell lung cancer (NSCLC). We performed immune-related gene expression profiling (irGEP) for ALK-rearranged NSCLC to assess the characteristics of the tumor microenvironment and explore potential therapeutic avenues.
PATIENTS AND METHODS: This study analyzed tumor samples from the ALCURE trial, a prospective observational study examining the efficacy of and mechanisms of resistance to alectinib in patients with ALK-rearranged NSCLC. The irGEP analysis was performed with a panel encompassing 750 immune-related genes.
RESULTS: Tumor samples from 52 of the 249 ALCURE trial patients were analyzed. Tumors with high CD8A expression showed upregulation of SNAI1 and downregulation of CDH1, with these genes encoding an epithelial-mesenchymal transition (EMT)-related transcription factor and E-cadherin, respectively, suggestive of EMT progression in these tumors. Tumors with high CD8A expression also manifested downregulation of genes related to tumor angiogenesis, including ANGPT2 (angiopoietin-2) and FLT1 (VEGF receptor 1), suggestive of a quiescent angiogenic state that may facilitate the recruitment of CD8+ T cells. Progression-free survival on alectinib appeared longer in patients with high than in those with low CD8A expression; however, this difference was not statistically conclusive (HR, 0.49 [95% CI, 0.18-1.35]).
CONCLUSIONS: CD8+ T cell infiltration may be associated with the alectinib efficacy in ALK-rearranged NSCLC. Anti-angiogenic therapies may enhance antitumor immunity and thereby augment the efficacy of alectinib as well as that of ICIs for such tumors.

Keywords:  Anaplastic lymphoma kinase; Immunotherapy; Non-small cell lung cancer; Tumor microenvironment; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.lungcan.2026.109416
Exp Cell Res. 2026 Apr 16. pii: S0014-4827(26)00141-2. [Epub ahead of print]459(2): 115024

GFPT1 facilitates immune escape in lung adenocarcinoma by promoting the O-GlcNAcylation of MYC and regulating PD-L1.

Wei Xu, Hui Hao, Fei Chi, Chaoran Xia, Shujun Zheng, Wei Liu, Tao Cai, Xinyan Liu.

  Lung adenocarcinoma (LUAD) is a leading cause of cancer-related death worldwide. Immunotherapies that overcome tumor immune evasion have emerged as promising strategies. GFPT1, the rate-limiting enzyme of the hexosamine biosynthetic pathway, is commonly dysregulated in malignancies. The aim of this work is to investigate the functional significance and molecular basis of GFPT1 in immune escape of LUAD. GFPT1 expression was evaluated through integrated bioinformatic analysis and validation in clinical specimens. Functional assays were employed to assess tumor cell-mediated immune evasion. Mmechanistic investigations were supported by molecular assays and in vivo models. We demonstrated that elevated GFPT1 expression in LUAD promotes immune escape of tumor cells. Mechanically, GFPT1 stabilized the expression of MYC by O-GlcNAcylation of MYC, thereby contributing to LUAD progression. Overall, this study revealed the promoting effect of GFPT1 on the immune escape of LUAD, which provided new therapeutic targets for the immunotherapy of LUAD.

Keywords:  GFPT1; Immune escape; Lung adenocarcinoma; MYC; O-GlcNAcylation

DOI:  https://doi.org/10.1016/j.yexcr.2026.115024
Toxicol Appl Pharmacol. 2026 Apr 19. pii: S0041-008X(26)00124-9. [Epub ahead of print]511 117828

10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.

Siying Li, Kaihua Shi, Lei Huang, Ziqing Li, Zhuo Qin, Yanan Sun, Caifang Qin, Chunmei Wang, He Li, Jinghui Sun, Wei Liu, Jiping Wu, Zhihong Zhang.

  10-Gingerol (10-G) exhibits antitumor activity, yet its mechanism in non-small cell lung cancer (NSCLC) remains unclear. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. This study investigated the antitumor mechanism of 10-G in NSCLC, emphasizing its dual role in activating lysosomes and inducing ferroptosis. In this study, we found 10-G induced ferroptosis in NSCLC by increasing iron accumulation, lipid peroxidation, intracellular ROS levels, and malondialdehyde (MDA) production, while depleting glutathione (GSH) and rising Fe2+ levels. Mechanistically, 10-G induced the dephosphorylation of Transcription Factor EB (TFEB) and TFEB dissociation from the 14-3-3 protein, thereby promoting the nuclear translocation of TFEB and the activation of lysosomal gene expression. Subsequently, the activation of lysosomes promoted the degradation of Nuclear factor erythroid 2-related factor 2 (NRF2), thereby affecting the expression levels of downstream targets Glutathione Peroxidase 4 (GPX4) and cystine/glutamate antiporter SLC7A11 (xCT), ultimately leading to ferroptosis. In vivo, 10-G suppressed tumor growth by inhibiting the TFEB-mediated NRF2/xCT/GPX4 axis and promoting ferroptosis. These findings demonstrated that 10-G suppressed the progression of NSCLC by promoting TFEB-mediated lysosomal degradation of NRF2, thereby inducing ferroptosis, which provides a rationale for a novel potential therapeutic strategy.

Keywords:  10-Gingerol; Ferroptosis; NRF2; NSCLC; TFEB

DOI:  https://doi.org/10.1016/j.taap.2026.117828
Front Med (Lausanne). 2026 ;13 1760300

Prognostic analysis and development of a prognostic model for EML4-ALK-positive lung cancer patients treated with ALK-TKIs.

Ruimin Liu, Chunrong Su, Hang Su, Lisen Wang.

   Objective: This study aimed to investigate prognostic factors and establish prognostic models for EML4-ALK-positive non-small cell lung cancer (NSCLC) patients receiving ALK tyrosine kinase inhibitors (TKIs) treatment.
Methods: We retrospectively analyzed 114 ALK-positive NSCLC patients treated at our institution from January 2020 to January 2024. Clinical data, laboratory results, imaging findings, and follow-up records were collected. Progression-free survival (PFS) and overall survival (OS) served as primary endpoints. Statistical methods included Kaplan-Meier analysis, Cox regression modeling, and nomogram construction (70% training set, 30% validation cohort). Model performance was evaluated using Harrell's C-index, calibration curves, and time-dependent receiver operating characteristic (ROC) analysis.
Results: The median PFS was 30.97 months (95% CI: 25.43-36.52), while median OS was not reached. Multivariate analysis identified four independent PFS predictors: brain metastasis (HR = 2.15, p = 0.008), central lesion location (HR = 1.89, p = 0.013), tumor diameter >3 cm (HR = 1.76, p = 0.022), and lymphocyte-to-monocyte ratio ≤2.26 (HR = 1.92, p = 0.011). For OS, significant factors included brain metastasis (HR = 2.87, p = 0.002), CYFRA21-1 level (HR = 1.65, p = 0.028), and LMR (HR = 2.04, p = 0.007). The developed nomograms demonstrated good prognostic accuracy, with validation cohort C-indices of 0.73 (PFS) and 0.75 (OS). Time-dependent AUCs for 3-year PFS and 4-year OS prognostic were 0.79 and 0.78, respectively.
Conclusion: Our study established that brain metastasis status, tumor characteristics, and systemic inflammatory markers significantly impact clinical outcomes in ALK-positive NSCLC patients undergoing TKI therapy. The developed prognostic models show satisfactory prognostic performance and may assist in clinical decision-making and patient stratification. These findings warrant further validation in prospective, multicenter studies.

Keywords:  ALK-TKIs; EML4-ALK; lung cancer; prognosis; prognostic model

DOI:  https://doi.org/10.3389/fmed.2026.1760300