bims-meluca 2026-11-08 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–11–08
six papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Circulating lipocalin-2 is associated with systemic inflammation and cachexia-related features in patients with gastrointestinal cancer.
Exercise-induced metabolic reprogramming in lung cancer and its translational implications for therapeutic advancement.
Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy.
NUB1 Regulates Muscle Atrophy in Lung Cancer Cachexia via NF-κB Signaling Pathway.
Cancer cells acquire cysteine directly from a reduced tumor microenvironment.
The modulation of PERK/ATF4/CHOP signaling by Neurokinin 3 receptor antagonists to ameliorate hepatic steatosis and endocrine dysfunction in PMOS mice - targeting the implication of endoplasmic reticulum stress.

Front Nutr. 2026 ;13 1937525

Circulating lipocalin-2 is associated with systemic inflammation and cachexia-related features in patients with gastrointestinal cancer.

Federica Tambaro, Giovanni Imbimbo, Dario Coletti, Roberta De Tullio, Elena Belloni, Giuseppe Nigri, Paola Costelli, Maurizio Muscaritoli, Alessio Molfino.

   Background: Cancer-associated anorexia (AN) and cachexia are frequent and debilitating complications of cancer, driven by systemic inflammation and metabolic dysregulation. Lipocalin 2 (LCN2) has been implicated in immune-metabolic integration and central appetite control, however data in cancer patients are limited. This study aimed to assess circulating LCN2 in patients with gastrointestinal cancers (GI-CP) and to evaluate its association with AN, levels of systemic inflammatory cytokines (IL-6, -8, -10, -15, -18, and TNF-α), body weight change, and level of muscularity.
Methods: Twenty-eight GI-CP naïve to treatment and 10 controls were enrolled. AN was diagnosed in 50% of GI-CP by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) score ( ≤ 30). Serum LCN2 concentrations were measured by ELISA, and cytokines were quantified using xMAP assay. Clinical, nutritional, and body composition parameters assessed by CT-scan were collected, and association(s) between LCN2 and inflammatory markers were analyzed.
Results: In GI-CP, predominantly represented by colorectal cancer, LCN2, IL-6, IL-8, IL-15, and TNF-α were higher than controls (p < 0.05). In GI-CP, LCN2 showed positive correlations with IL-6 (rho = 0.862; p < 0.001) and IL-8 (rho = 0.789; p < 0.001). LCN2 levels were higher in GI-CP with AN vs. control (p = 0.003), but not between anorexic vs. non-anorexic GI-CP, and in GI-CP with body weight loss compared to those with weight-stable (p = 0.031) and vs. controls (p < 0.001). LCN2 was higher in GI-CP with AN and body weight loss compared to those without AN and body weight stable (p = 0.046) and in GI-CP with low muscle mass and body weight loss compared with those with body weight stable and high muscularity (p = 0.028).
Conclusion: Overall, these findings suggest that LCN2 may reflect the combined burden of inflammation and cachexia-related features in GI cancer.

Keywords:  anorexia; cachexia; cytokines; gastrointestinal cancer (GI); lipolocalin-2; muscle wasting; systemic inflamamtion

DOI:  https://doi.org/10.3389/fnut.2026.1937525
J Transl Med. 2026 Aug 06. pii: 1389. [Epub ahead of print]24(1):

Exercise-induced metabolic reprogramming in lung cancer and its translational implications for therapeutic advancement.

Yonghua Zheng, Yisheng Chen, Hanyang Zhao, Guanghui Wu, Chen Hua, Fu Gao, Yue Liu, Lei Jiang, Lihua Dai.

  Lung cancer remains one of the leading causes of cancer-related mortality worldwide, characterized by profound metabolic reprogramming that sustains malignant growth, immune evasion, and therapeutic resistance. Aberrant activation of glycolysis, increased fatty acid synthesis and uptake, and dysregulated glutamine metabolism provide energy and biosynthetic substrates while reshaping the tumor microenvironment through lactate accumulation, acidosis, and angiogenic signaling. Experimental and clinical evidence indicates that exercise may modulate aspects of these oncogenic metabolic pathways, enhance mitochondrial oxidative capacity, improve oxygen delivery, and restore systemic metabolic homeostasis. By modulating glycolytic flux, lipid turnover, and amino acid metabolism, exercise exerts comprehensive effects on both tumor cells and the host, alleviating cancer-associated cachexia, improving insulin sensitivity, and suppressing systemic inflammation. Exercise may also enhance immune competence and vascular function, thereby potentially promoting antitumor surveillance and supporting the therapeutic response.Integrated with conventional treatments such as chemotherapy, radiotherapy, and immunotherapy, exercise may serve as a non-pharmacological metabolic adjuvant that increases treatment tolerance, mitigates adverse effects, and improves quality of life. Furthermore, exercise-related metabolic, molecular, and physiological biomarkers, including glucose and lipid indices, insulin sensitivity parameters, irisin, cardiopulmonary performance indicators, and serum glycosylation profiles, offer promising tools for evaluating metabolic states and guiding personalized interventions. Collectively, these findings underscore exercise as a powerful modulator of tumor and host metabolism, aligning with the translational paradigm that bridges mechanistic discovery and clinical application. Future research should focus on defining standardized exercise prescriptions, validating predictive biomarkers, and elucidating subtype-specific responses to facilitate the integration of precision exercise therapy into lung cancer management.

Keywords:  Exercise therapy; Fatty acid metabolism; Glycolysis; Lung cancer; Metabolic reprogramming; Translational medicine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-026-08665-2
bioRxiv. 2026 Oct 27. pii: 2026.10.24.761570. [Epub ahead of print]

Targeting alpha-ketoglutarate starvation within the tumor-immune microenvironment rescues T cell effector function in cancer immunotherapy.

Katarina Benejova, Kristina Travis, Deepti Mathur, No Joon Song, Zihai Li, Mitch A Phelps, Elaine Mardis, Liza Makowski, David P Carbone, Dwight H Owen, Martin Benej.

Given its status as the leading cause of global cancer mortality, there is a critical need to enhance immunotherapy strategies for lung cancer to overcome widespread resistance to current treatments. Immunotherapy recruits the patient's immune system to attack and destroy cancer cells. While highly effective in a subset of patients, chronic exposure of immune cells to cancer cells leads to a progressive loss of effector T cell function and progression of T cell exhaustion; now considered two well-established hallmarks of immunotherapy resistance. The tumor-immune microenvironment (TIME)-driven differentiation into the exhausted T cell phenotype is marked by a loss of metabolic plasticity and epigenome-wide changes in distribution of repressive histone marks such as histone H3 subunit methylation at lysine 27 (H3K27me 3 ). Here, we studied how these processes are connected to metabolite availability within the TIME. In vitro , chronic antigen stimulation and hypoxia led to rapid loss of effector function, associated with a suppression of alpha-ketoglutarate (aKG) intracellular concentrations in T cells. Supplementation of cell-permeable aKG led to a rescue of effector cytokine production and to improved cytotoxic capacity despite chronic antigen stimulation and hypoxia. Increased intracellular aKG levels restored the activity of H3K27 demethylases UTX and JMJD3, consistent with epigenome-wide decreased H3K27me 3 . In vivo , dietary supplementation with commercially available calcium-aKG (Ca-aKG) supplements led to an elevation of serum and intratumoral aKG levels associated with a significant increase of immunotherapy effectiveness in mouse models of NSCLC. Clinical samples from patients with NSCLC contained significantly decreased serum aKG levels in older NSCLC patients (>65 years of age). Analysis identified a novel association between serum aKG levels and poor immunotherapy response. Thus, our work demonstrates that intratumoral metabolite "starvation" can be therapeutically exploited to improve immunotherapy outcomes in non-small cell lung cancer (NSCLC).

DOI: https://doi.org/10.64898/2026.10.24.761570
Adv Sci (Weinh). 2026 Oct 31. pii: e78492. [Epub ahead of print]

NUB1 Regulates Muscle Atrophy in Lung Cancer Cachexia via NF-κB Signaling Pathway.

Yuqi Han, Yaru Xia, Weiquan Li, Jiaming Wu, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Xuejiao Dong, Jiemin Li, Yu Jiao, Guixiao Huang, Xiaoping Zhang, Hongmei Yang.

  Cancer-associated cachexia (CAC) is a devastating multifactorial syndrome characterized by progressive skeletal muscle atrophy. Its mechanisms remain incompletely clarified, with limited effective therapeutic targets. NUB1, a negative regulator of ubiquitin-like proteins mediating protein degradation, has not been fully elucidated in CAC-induced muscle atrophy. Here, NUB1 was significantly upregulated in skeletal muscles of Lewis lung carcinoma (LLC) cachexia mice and C2C12 myotube atrophy models stimulated with LLC tumor-conditioned medium (LCM). Silencing NUB1 alleviated LCM-induced myotube atrophy in vitro and enhanced muscle mass, fiber cross-sectional area and function in LLC cachectic mice in vivo. Mechanistically, upregulated NUB1 recruited IκBα to bind proteasomal subunit S5a, promoting IκBα degradation, thus increasing NF-κB nuclear translocation and transcription of Atrogin1 and MuRF1. Silencing NUB1 inhibited NF-κB activation, while TNFα reversed its protective effect. These findings identified NUB1 as a novel driver of CAC-related muscle atrophy and highlighted the NUB1/IκBα/NF-κB axis as a promising therapeutic target.

Keywords:  NF‐κB signaling; NUB1; cancer‐associated cachexia; muscle atrophy

DOI:  https://doi.org/10.1002/advs.78492
bioRxiv. 2026 Oct 27. pii: 2026.10.25.761647. [Epub ahead of print]

Cancer cells acquire cysteine directly from a reduced tumor microenvironment.

Feroza K Choudhury, Basma A Yasseen, Paloma González-Sánchez, Meredith Long, Samantha Caldwell, Pritin N Soni, Suehelay Acevedo-Acevedo, Yun Huang, Elsa R Flores, Chang Jiang, Nathan P Ward, Gina M DeNicola.

The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.

DOI: https://doi.org/10.64898/2026.10.25.761647
J Physiol Biochem. 2026 Nov 03. pii: 113. [Epub ahead of print]82(1):

The modulation of PERK/ATF4/CHOP signaling by Neurokinin 3 receptor antagonists to ameliorate hepatic steatosis and endocrine dysfunction in PMOS mice - targeting the implication of endoplasmic reticulum stress.

Taniya Fernando, Jiahui Pan, Zhentao Gong, Lingshan Zhang, Fei Guo, Mingqing Li, Xiaoyong Zhu, Yingli Shi.

  Lipotoxicity contributes to polyendocrine metabolic ovarian syndrome (PMOS) pathogenesis by inducing hyperandrogenism (HA) and insulin resistance (IR), while excess testosterone triggers endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in PMOS models. However, ER stress and UPR activation under HA-obese conditions remain unexplored in granulosa cells (GCs) and PMOS mouse liver and ovary. Neurokinin 3 receptor antagonists (NK3Ra) reverse PMOS metabolic and reproductive impairments; therefore we established an HA-obese model by exposing KGN cells to palmitic acid (PA) and dihydrotestosterone (DHT), and an HFD-letrozole PMOS mouse model, both treated with NK3Ra. In KGN cells, ER and mitochondrial ultrastructure disruption was observed by TEM, UPR sensor protein and gene expression/phosphorylation was analyzed by qPCR and western blotting, and NK3Ra rescue of cell viability was evaluated, alongside peripheral and tissue biochemical/hormonal assays, immunohistochemistry for AMH, UPR sensor and cascade proteins, and redox metabolism assays. NK3Ra alleviated ER stress by modulating the PERK-ATF4-CHOP axis, improving steroidogenesis, redox homeostasis, and viability in HA-obese models. In PMOS mice, hepatic steatosis was reversed with associated downregulation of CHOP, decreased de novo lipogenic gene expression, and increased superoxide dismutase activity, while estrous cyclicity and steroid hormone metabolism were restored, accompanied by reduced ovarian ATF4, CHOP, and GRP78 expression by NK3Ra activity. Collectively, our findings suggest that NK3Ra alleviates lipotoxic-HA-induced ER stress via the modulation of the PERK-ATF4-CHOP pathway, thereby ameliorating metabolic and endocrine aberrations in PMOS.

Keywords:  Endoplasmic reticulum stress; Hepatic steatosis; Hyperandrogenism; Neurokinin 3 receptor antagonist; Obesity; Polyendocrine metabolic ovarian syndrome

DOI:  https://doi.org/10.1007/s13105-026-01252-5