bims-meluca 2026-07-19 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2026–07–19
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Prognostic value of perioperative inflammatory biomarkers in patients undergoing surgical resection for non-small cell lung cancer.
Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
The MAPK/ATF3/ASNS axis drives amino acid metabolic reprogramming to promote NSCLC survival under glucose deprivation.
KRAS Mutation Subtypes, Co-Mutations, PD-L1 Expression, and Survival Outcomes in Non-Small Cell Lung Cancer.
Macrophage-Myocyte Cross Talk Induces M1 Polarization and Inflammatory Cytokine Production During Cancer Cachexia.
Association between GDF-15 and sarcopenia progression in older adults: results from a population-based study.
PPP2R2C promotes aerobic glycolysis and mediates pemetrexed resistance in lung adenocarcinomas by upregulating TCP1-dependent protein folding of glycolytic enzymes.
Integrating chemokine signatures and multi-omic biomarkers to predict immunotherapy response in non-small cell lung cancer: a comprehensive narrative review.

J Thorac Dis. 2026 Jun 30. 18(6): 605

Prognostic value of perioperative inflammatory biomarkers in patients undergoing surgical resection for non-small cell lung cancer.

Jianxin Cai, Jiahua Tu, Ronglong Lin, Jianxin Xu.

   Background: Systemic inflammation plays a pivotal role in tumor progression and patient prognosis in non-small cell lung cancer (NSCLC). While preoperative inflammatory biomarkers have demonstrated prognostic utility, the additional value of perioperative dynamic changes remains insufficiently characterized. This study aimed to evaluate the prognostic significance of both preoperative inflammatory biomarkers and their perioperative alterations in patients undergoing curative-intent surgical resection for NSCLC.
Methods: We conducted a retrospective cohort study of 368 consecutive patients who underwent surgical resection for pathologically confirmed NSCLC at our institution between January 2022 and December 2024. Preoperative blood samples were analyzed for complete blood count, C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6). Inflammatory indices including neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and prognostic nutritional index (PNI) were calculated. Perioperative changes (Δ) were determined from postoperative day 1 values. Primary endpoints were disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS) at 12 months. Kaplan-Meier analysis with log-rank tests and Cox proportional hazards regression were employed for survival analysis.
Results: The median follow-up was 12.0 months. At 12 months, the DFS, RFS, and OS rates were 48.4%, 63.9%, and 75.0%, respectively. In univariate analysis, elevated NLR [≥2.78; hazard ratio (HR) =1.97, 95% confidence interval (CI): 1.48-2.62, P<0.001], elevated SII (≥585; HR =1.81, 95% CI: 1.35-2.42, P<0.001), low PNI (<47.8; HR =1.70, 95% CI: 1.28-2.27, P<0.001), elevated IL-6 (≥9.8 pg/mL; HR =1.71, 95% CI: 1.19-2.46, P=0.004), and high ΔNLR (≥7.8; HR =2.07, 95% CI: 1.50-2.85, P<0.001) were significantly associated with inferior DFS. Multivariate analysis identified advanced stage (IIB-IIIA; HR =1.41, 95% CI: 1.02-1.95, P=0.04), low PNI (HR =1.62, 95% CI: 1.21-2.17, P=0.001), elevated IL-6 (HR =1.67, 95% CI: 1.15-2.41, P=0.007), and high ΔNLR (HR =1.69, 95% CI: 1.15-2.50, P=0.008) as independent prognostic factors for DFS. The combined inflammatory index achieved superior discriminatory performance [area under the curve (AUC) =0.712] compared with individual markers.
Conclusions: Perioperative inflammatory biomarkers, particularly the combination of preoperative PNI, IL-6, and perioperative ΔNLR, provide robust prognostic stratification in surgically resected NSCLC. Integration of these readily accessible biomarkers into clinical decision-making may facilitate personalized surveillance strategies and adjuvant therapy selection.

Keywords:  Non-small cell lung cancer (NSCLC); inflammatory biomarkers; interleukin-6 (IL-6); neutrophil-to-lymphocyte ratio (NLR); prognostic nutritional index (PNI)

DOI:  https://doi.org/10.21037/jtd-2026-0664
Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00106-7. [Epub ahead of print] 102422

Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.

Emma Frank, Kaspar W Persson, Pauline Morigny, Zakarias Kefil Jensen Ogueboule, Tang Cam Phung Pham, Jonas R Knudsen, Maria Rohm, Lykke Sylow, Steffen H Raun.

   PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice with anorexia compared to weight stable C26-cancer mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.

Keywords:  Cancer cachexia; food restriction; glucose metabolism; insulin sensitivity; muscle

DOI:  https://doi.org/10.1016/j.molmet.2026.102422
J Transl Med. 2026 Jul 11.

The MAPK/ATF3/ASNS axis drives amino acid metabolic reprogramming to promote NSCLC survival under glucose deprivation.

Fuzhi Yang, Hao Qin, Xuelin Zhang, Yun Zhao, Shuai Jiang, Xiaoyu Chen, Zheng Li, Jing Wang, Dongfang Tang, Wen Gao, Xunxia Zhu, Xiaoyong Shen.

   BACKGROUND: Glucose deprivation is a prevalent stressor within the tumor microenvironment. Nonetheless, the fundamental mechanism through which non-small cell lung cancer (NSCLC) cells orchestrate survival and progression through specific metabolic hubs under such conditions remains poorly understood.
METHODS: This study utilized integrated multiomics analyses, encompassing transcriptomics and metabolomics, to identify pivotal targets. Functional validation was performed via in vitro assays, including CCK-8, colony formation, Transwell, and EdU assays, as well as in vivo models, such as subcutaneous xenografts and tail-vein lung metastasis models. The function and mechanism of the MAPK/ATF3/ASNS signaling axis were comprehensively investigated using gene knockdown/overexpression techniques, Western blotting, immunohistochemistry, and metabolomic analysis.
RESULTS: Combined transcriptomic and metabolomic analyses revealed that glucose deprivation markedly upregulates ASNS expression in NSCLC cells, correlating with unfavorable patient outcomes. Functionally, both in vitro and in vivo experiments confirmed that ASNS significantly promotes the malignant behaviors of NSCLC cells under glucose-deprived conditions. Metabolomic analysis revealed that ASNS supports tumor cell survival during energetic stress by maintaining a dynamic balance of multiple amino acids. Mechanistically, glucose deprivation activates the MAPK signaling pathway, leading to the upregulation of the transcription factor ATF3, which binds directly to the ASNS promoter and transcriptionally activates its expression, thereby promoting malignant progression in NSCLC. Finally, the combined targeting of glucose metabolism using 2-DG, along with ASNS inhibition, demonstrated additive antitumor efficacy in vivo.
CONCLUSION: The results of this study revealed that, under glucose deprivation stress, the MAPK/ATF3/ASNS axis functions as a critical signaling-metabolic hub, promoting NSCLC progression by driving amino acid metabolic reprogramming. Targeting this axis offers a novel strategy for intervening in tumor metabolic adaptation and developing innovative combination therapies.

Keywords:  Amino acid metabolic reprogramming; Asparagine synthetase (ASNS); Glucose deprivation; MAPK; Non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.1186/s12967-026-08551-x
J Clin Med. 2026 Jul 04. pii: 5236. [Epub ahead of print]15(13):

KRAS Mutation Subtypes, Co-Mutations, PD-L1 Expression, and Survival Outcomes in Non-Small Cell Lung Cancer.

Nesrin Gürçay, Funda Demirağ, Müzeyyen Burcu Kaplan Yılmaz, İlknur Öz, Tuba İnal Cengiz, Abdulkadir Koçanoğlu, Serdar Karakaya, Ömer Faruk Demir.

  Background: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and are associated with substantial molecular and immunological heterogeneity. However, the clinicopathological associations and prognostic relevance of KRAS mutation subtypes and co-occurring genomic alterations in relation to PD-L1 expression and survival outcomes remain incompletely understood, particularly in the immunotherapy era. Methods: This retrospective single-center study included 93 KRAS-mutant NSCLC patients identified among 543 consecutively sequenced cases between March 2024 and March 2025. KRAS mutation subtypes, co-mutations involving TP53, STK11, and KEAP1, PD-L1 expression status, clinicopathological features, and survival outcomes were evaluated. Overall survival was assessed using Kaplan-Meier analysis and Cox proportional hazards regression models. Results: KRAS mutations were detected in 17.1% of NSCLC patients. G12C was the most frequent KRAS subtype (38.7%), followed by G12V (18.3%) and G12D (14.0%). Co-occurring mutations were identified in 73.1% of cases, most commonly involving TP53 (40.9%) and STK11 (33.3%). PD-L1 expression was negative in 48.4% of patients, low in 28.0%, and high in 23.7%. No significant association was identified between KRAS mutation subtype and PD-L1 expression (p = 0.663). STK11-mutated tumors demonstrated a trend toward lower PD-L1 expression levels compared with STK11 wild-type tumors. However, none of the molecular variables retained independent prognostic significance. Immunotherapy was associated with significantly prolonged overall survival (median OS: 24 vs. 7 months, p = 0.013) and remained independently associated with improved survival in multivariate analysis (HR: 0.376, 95% CI: 0.204-0.694, p = 0.002). Advanced-stage disease independently predicted worse survival outcomes (HR: 13.43, 95% CI: 1.81-99.79, p = 0.011). Conclusions: KRAS mutation subtypes and co-occurring genomic alterations demonstrated limited independent prognostic significance in this real-world NSCLC cohort. In contrast, immunotherapy was associated with improved overall survival in this retrospective cohort. These findings should be interpreted as observational and hypothesis-generating rather than evidence of predictive treatment benefit. Larger prospective studies integrating genomic and immune biomarkers are warranted.

Keywords:  KRAS; NSCLC; PD-L1; STK11; TP53; co-mutation; immunotherapy

DOI:  https://doi.org/10.3390/jcm15135236
Mediators Inflamm. 2026 ;2026(1): e6461737

Macrophage-Myocyte Cross Talk Induces M1 Polarization and Inflammatory Cytokine Production During Cancer Cachexia.

Se-Eun Bae, Miyong Yun, Min Ju Kang, Sang Woo Woo, Do Won Kim, Eun-Ok Kim, Hyeon Soo Kim.

Cancer cachexia (CC) significantly reduces survival in patients with cancer, and intramuscular inflammation plays an important role in disease progression. Macrophages, as key mediators of the innate immune response, contribute to muscle inflammation by secreting pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), in response to various stimuli. Despite their importance, the mechanisms of macrophage polarization within the cachectic skeletal muscle and the subsequent impacts on muscle inflammation remain poorly understood. In this study, we used a murine model of CC to explore the interaction between macrophages and myocytes during muscle inflammation. Our results demonstrate that cachectic myocytes recruit M1-polarized macrophages that amplify local inflammation via the secretion of IL-1β, IL-6, and TNF-α. These findings underscore the pivotal role of macrophage-derived cytokines in the pathogenesis of cancer-induced muscle inflammation and suggest that targeting macrophage-driven inflammatory pathways may be an effective therapeutic strategy for mitigating muscle wasting in CC.

DOI: https://doi.org/10.1155/mi/6461737
EBioMedicine. 2026 Jul 17. pii: S2352-3964(26)00283-5. [Epub ahead of print]130 106399

Association between GDF-15 and sarcopenia progression in older adults: results from a population-based study.

Yuh-Shiou Gu, Alice Margherita Ornago, Caterina Gregorio, Chiara Ceolin, Anna Picca, Riccardo Calvani, Emanuele Marzetti, Birger C Forsberg, Davide Liborio Vetrano.

   BACKGROUND: Growth differentiation factor-15 (GDF-15), a stress-induced cytokine, has been implicated in pathways related to muscle degeneration, although findings regarding its association with sarcopenia remain heterogeneous. This study investigated the association between serum levels of GDF-15 and sarcopenia progression in community-dwelling older adults.
METHODS: 2347 individuals (mean age 72.3 years [SD 10.4]; 61.6% women), participating in the Swedish National Study on Aging and Care in Kungsholmen, were included in the study. Sarcopenia status (no, probable, and confirmed sarcopenia) were defined according to modified European Working Group on Sarcopenia in Older People 2 criteria. Twelve-year longitudinal sarcopenia trajectories were identified through latent class analysis. GDF-15 was measured in serum samples collected at baseline. Logistic regression was employed to assess the associations between GDF-15 and sarcopenia progression.
FINDINGS: Two trajectories of sarcopenia were identified: an early-progression pattern around the age of 70 and a later-progression pattern around the age of 80. Baseline sarcopenia prevalence differed between trajectories (p < 0.001), and GDF-15 levels were higher in the early trajectory (1.00 ng/mL vs. 0.86 ng/mL, p < 0.001). In adjusted multinomial logistic models, higher GDF-15 was associated with greater odds of probable (aOR = 1.6; 95% CI: 1.2-2.0) and confirmed sarcopenia (aOR = 1.9; 95% CI: 1.3-2.6). GDF-15 levels were also linked to increased odds of belonging to the early progression trajectory (aOR = 1.5; 95% CI: 1.2-1.9), with the association driven by the highest quintiles.
INTERPRETATION: GDF-15 reflects biological processes linked to muscle degeneration and may provide complementary information alongside established measures of sarcopenia in community-dwelling older adults.
FUNDING: The Swedish Research Council, the Swedish Ministry of Health and Social Affairs, and the County Councils and Municipalities.

Keywords:  Biomarker; Disease progression; Growth differentiation factor 15; Trajectory

DOI:  https://doi.org/10.1016/j.ebiom.2026.106399
Respir Res. 2026 Jul 16.

PPP2R2C promotes aerobic glycolysis and mediates pemetrexed resistance in lung adenocarcinomas by upregulating TCP1-dependent protein folding of glycolytic enzymes.

Jia Chen, Xiaoshan Wang, Zhengyang Wang, Gang Li, Fei Han.

   BACKGROUND: Lung adenocarcinoma (LUAD) remains lethal primarily due to its tendency for early metastasis and the universal development of chemotherapy resistance. The results of this study delineate a coherent signaling axis, originating from the upregulation of PPP2R2C expression to metabolic reprogramming, which ultimately influences the malignant progression and chemotherapy resistance of LUAD.
METHODS: GEPIA analysis was used to evaluate PPP2R2C expression in NSCLC. Following shRNA-mediated knockdown, cell proliferation, migration, apoptosis, and glycolytic activity were assessed in NCI-H1299 and A549 cells. Subcutaneous tumor formation was evaluated four weeks after injection of LV-shPPP2R2C or control vector, followed by H&E staining and immunohistochemical analysis of PPP2R2C and Ki67.
RESULTS: Clinical analysis shows that PPP2R2C is highly expressed in LUAD and is associated with poor prognosis, lymph node metastasis, and advanced disease stage. In vitro knockdown of PPP2R2C suppresses proliferation and migration and promotes apoptosis. Mechanistically, PPP2R2C drives the Warburg effect by upregulating the molecular chaperone TCP1 to ensure proper folding of glycolytic enzymes. Blocking TCP1 or glycolysis (with 2-DG) reverses PPP2R2C-mediated survival advantage and pemetrexed resistance. In vivo experiments confirm that knocking down PPP2R2C or TCP1 similarly inhibits tumor growth and restores chemotherapy sensitivity.
CONCLUSIONS: In summary, the results elucidate a novel mechanism whereby PPP2R2C enhances glycolysis by regulating TCP1-dependent protein refolding, thereby driving LUAD progression and chemoresistance. Thus, this study establishes a strong rationale for targeting this pathway as a potential therapeutic approach.

Keywords:  Aerobic glycolysis; Drug-resistance; LUAD; PPP2R2C; Protein folding

DOI:  https://doi.org/10.1186/s12931-026-03681-8
Front Oncol. 2026 ;16 1830731

Integrating chemokine signatures and multi-omic biomarkers to predict immunotherapy response in non-small cell lung cancer: a comprehensive narrative review.

Luis Cabezón-Gutiérrez, Magda Palka-Kotlowska, Sara Custodio-Cabello, Adriana Carolina Rosero-Rodriguez, Beatriz Chacón-Ovejero.

  Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized the therapeutic landscape, only 20-30% of unselected patients achieve durable clinical benefits. Given the imperfect predictive value of traditional markers, such as PD-L1 expression and tumor mutational burden, there is an urgent need for multidimensional biomarkers to guide personalized immunotherapy. This review evaluates emerging predictive tools, with a specific focus on chemokine signatures and multi-omic (genomic, transcriptomic, proteomic, and metabolomic) biomarkers, including integrative models. By examining the biological rationale linking tumor microenvironment chemokine networks to antitumor immunity, we discuss recent advances in profiling that enable comprehensive predictive signatures. A comprehensive narrative literature search of PubMed and EMBASE (2015-2026) was performed to identify relevant peer-reviewed studies, clinical trials, and computational analyses. Evidence suggests that integrating chemokine profiles with multi-omic data holds significant promise for improving patient selection. Multidimensional models incorporating tumor genomics and immune microenvironment features are likely to outperform single-analyte tests in identifying ICI responders. Despite ongoing challenges, such as tumor heterogeneity, assay standardization, and data integration complexity, the development of liquid biopsies and advanced machine learning models offers a path toward robust, clinically applicable predictive nomograms, which are expected to refine immunotherapy decision-making and significantly improve clinical outcomes for patients with NSCLC.

Keywords:  NSCLC; biomarkers; chemokines; immunotherapy; multi-omics; precision oncology; predictive biomarkers; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1830731