bims-meluca 2026-09-20 papers

Trends Cancer. 2026 Sep 15. pii: S2405-8033(26)00207-4. [Epub ahead of print]

Lkb1 loss links dietary lipids to cancer cachexia.

Cancer cachexia involves more than a caloric deficit. A recent study by Cross et al. in Science shows that dietary lipid composition exacerbates cachexia in LKB1/STK11-deficient lung cancer through local prostaglandin E2 production and pulmonary sensory neuron activation. By linking local lipid metabolism to anorexia and wasting, these findings support precision nutritional interventions for cancer cachexia.

Keywords: Lkb1/Stk11 deficiency; PGE(2); cancer cachexia; dietary lipid; sensory neurons

DOI: https://doi.org/10.1016/j.trecan.2026.08.011

Int Immunol. 2026 Sep 16. pii: dxag048. [Epub ahead of print]

STK11 deficiency drives NSCLC immune resistance via ETNK2-mediated phosphoethanolamine accumulation.

Wei Zhang, Jing Hu, Zhengbin Zhang.

STK11/LKB1 mutations are critical drivers of primary resistance to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC); however, the metabolic mechanisms by which STK11 deficiency remodels the tumor microenvironment (TME) to induce an immunosuppressive state remain largely elusive. By performing metabolomics and liquid chromatography-mass spectrometry (LC-MS) analysis on tumor interstitial fluid (TIF) from STK11-deficient patient-derived xenograft (PDX) and syngeneic mouse CMT167 models, we investigated the metabolic landscape and its impact on CD8+ T cell functionality. We further integrated biochemical assays (ChIP, Co-IP, and dual-luciferase) and engineered small extracellular vesicles (sEVs) to dissect the upstream regulatory network and evaluate therapeutic potential. We identified a significant and specific accumulation of phosphoethanolamine (pEtn) in the STK11-deficient TIF, which directly impairs CD8+ T cell effector functions by downregulating membrane diacylglycerol (DAG) and blocking proximal T cell receptor (TCR) signaling. Mechanistically, STK11 loss triggers mitochondrial reactive oxygen species (ROS) accumulation, which inhibits prolyl hydroxylases (PHDs) and prevents the VHL-mediated degradation of HIF1A. Stabilized HIF1A subsequently recruits the demethylase TET1 to the ETNK2 promoter, driving its epigenetic activation and excessive pEtn synthesis. Clinical analyses confirm that high ETNK2 expression correlates with poor ICI response and shortened survival. Targeted delivery of siETNK2 via EGFR-targeted exosomes effectively lowered TIF pEtn concentrations, restored T cell activity, and sensitized STK11-deficient tumors to PD-1 blockade in vivo. This study elucidates a novel "mitochondrial ROS-HIF1A-TET1-ETNK2" metabolic-epigenetic axis, providing a precise interventional strategy to overcome genotype-specific immune resistance in NSCLC.

Keywords: Exosome; Immune checkpoint inhibitor resistance

DOI: https://doi.org/10.1093/intimm/dxag048

Int Immunopharmacol. 2026 Sep 16. pii: S1567-5769(26)01270-1. [Epub ahead of print]189 117423

KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.

Nanding Yu, Yingxiao Wu, Mengling Li, Yang Liu, Weidong Wu, Xiangqi Chen.

AIMS: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options. Ferroptosis has emerged as a promising antitumor strategy. However, the metabolic determinants governing ferroptotic vulnerability in LUSC remain incompletely understood. We investigated glucose-6-phosphate dehydrogenase (G6PD) in this context.
MATERIALS AND METHODS: In vitro models using small interfering RNA (siRNA)-mediated G6PD depletion, together with pharmacological studies using 6-aminonicotinamide (6-AN) and LUSC xenograft models, were employed to investigate the underlying mechanisms.
KEY FINDINGS: G6PD was markedly upregulated in LUSC, and analysis of the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort showed that elevated G6PD expression was associated with advanced clinicopathological features and poorer overall survival. While ferroptosis inducers (erastin and RSL3) did not alter G6PD mRNA, they robustly increased G6PD protein during ferroptotic stress. Genetic or pharmacological inhibition of G6PD significantly sensitized LUSC cells to RSL3-induced ferroptosis, evidenced by enhanced lipid peroxidation, glutathione depletion, and ferrostatin-1-reversible cell death. Mechanistically, G6PD inhibition led to mitochondrial ferrous iron accumulation, elevated reactive oxygen species, impaired respiration, and activation of PINK1/Parkin-dependent mitophagy, which further exacerbated ferroptotic injury. In vivo, combined treatment with 6-aminonicotinamide and RSL3 markedly suppressed LUSC xenograft growth and enhanced biochemical markers of ferroptotic stress. Furthermore, G6PD protects cells by positively regulating the cystine/glutamate antiporter SLC7A11 to maintain redox homeostasis. Upstream, the oncogenic factor Krüppel-like factor 5 (KLF5) directly activates G6PD transcription.
SIGNIFICANCE: Our findings identify a KLF5-G6PD-SLC7A11 axis as a critical metabolic safeguard against ferroptosis in LUSC. Targeting G6PD disrupts mitochondrial homeostasis, enhances mitophagy-dependent oxidative stress, and sensitizes tumors to ferroptotic therapy, highlighting a promising therapeutic strategy for LUSC.

Keywords: Ferroptosis; G6PD; KLF5; Lung squamous cell carcinoma

DOI: https://doi.org/10.1016/j.intimp.2026.117423

Sci Immunol. 2026 Sep 18. 11(123): eaea4179

In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity.

Wenlong Jia, Guanxing Yu, Shenqi Han, Zhibo Ma, Junnan Liang, Wei Yan, Xinling Zhang, Chenglong Zeng, Lin Xue, Feng Xia, Ganxun Li, Ran Tao, Peixiang Lan, Wei Yan, Wanguang Zhang, Huifang Liang, Xiaoping Chen, Zhao Huang, Bixiang Zhang.

Tumor cells often evade immune pressure via metabolic reprogramming, yet the key metabolic regulators orchestrating this process remain incompletely defined. Here, using in vivo metabolic CRISPR screening under distinct immune pressures, we identified tumor cell-intrinsic solute carrier family 1 member 5 (SLC1A5) as a metabolic node that sustains an immunosuppressive tumor microenvironment. SLC1A5-mediated glutamine metabolism in tumor cells modulated CD8 T cell infiltration and effector function, reshaping tumor responses to immune checkpoint blockade therapy. Glucose deprivation up-regulated SLC1A5 isoforms in tumor cells, enhancing glutamine uptake and glutathione synthesis. This adaptation limited mitochondrial oxidative stress and cytosolic mitochondrial DNA release, thereby suppressing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, interferon-β production, and CD8 T cell antitumor responses. These findings define a glutamine-fueled metabolic program as a barrier to tumor immunogenicity, positioning SLC1A5 as a tumor-intrinsic metabolic regulator with potential therapeutic relevance.

DOI: https://doi.org/10.1126/sciimmunol.aea4179