bims-meluca 2025-04-20 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2025–04–20
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Correlation Between Body Mass Index and Immunotherapy Response in Advanced NSCLC.
INFLAMMATION IN CANCER CACHEXIA: STILL THE CENTRAL TENET OR JUST ANOTHER PLAYER?
Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation.
Addition of metformin to anti-PD-1/PD-L1 drugs activates anti-tumor immune response in peripheral immune cells of NSCLC patients.
Hypoxia LUAD H1975 cell-derived exosomal miR-671-3p promotes angiogenesis via regulating KLF2-VEGFR2 axis.
Integrative metabolic profiling of hypothalamus and skeletal muscle in a mouse model of cancer cachexia.
Clinical and dynamic circulating cytokines profile features of long-term progression-free survival benefit to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Cancers (Basel). 2025 Mar 29. pii: 1149. [Epub ahead of print]17(7):

Correlation Between Body Mass Index and Immunotherapy Response in Advanced NSCLC.

Walid Shalata, Itamar Gothelf, Yulia Dudnik, Ahron Yehonatan Cohen, Ashraf Abu Jama, Tom Liba, Ofir Dan, Lena Tourkey, Sondos Shalata, Abed Agbarya, Amichay Meirovitz, Alexander Yakobson.

   BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Emerging evidence suggests a potential association between elevated body mass index (BMI) and enhanced ICI efficacy, yet this relationship remains inconclusive and warrants further investigation. This study aims to evaluate the impact of BMI on treatment efficacy and survival outcomes in advanced NSCLC patients treated with first-line ICI therapy.
METHODS: A retrospective study was conducted at a multi-center registry to evaluate the impact of baseline BMI on overall survival (OS) and progression-free survival (PFS) in patients with stage IV NSCLC who received first-line ICI therapies. Treatment regimens included pembrolizumab or the combination of ipilimumab and nivolumab, administered either as monotherapy or in combination with chemotherapy, at the oncology department between January 2018 and December 2023. BMI was categorized according to the World Health Organization (WHO) classification, and OS and PFS were evaluated using Kaplan-Meier survival analysis and the Cox proportional hazards regression model.
RESULTS: Among 346 patients, 12.72% were underweight, 45.38% normal weight, 29.19% overweight, and 12.72% obese. Overweight and obese patients were more likely to receive pembrolizumab (p = 0.039) and less likely to undergo chemotherapy (p = 0.012). No significant differences in median overall survival (OS, log-rank: p = 0.155) or progression-free survival (PFS, log-rank: p = 0.370) were observed across BMI categories. However, differences emerged upon further analysis of PD-L1 levels (OS, log-rank: p = 0.029; PFS, log-rank: p = 0.044), additional chemotherapy (OS, log-rank: p = 0.009; PFS, log-rank: p = 0.021), type of immune checkpoint inhibitor (OS, log-rank: p < 0.001; PFS, log-rank: p < 0.001), and histologic diagnosis (OS, log-rank: p = 0.011; PFS, log-rank: p = 0.003).
CONCLUSIONS: BMI was not an independent predictor of survival outcomes in advanced NSCLC treated with ICI. Incorporating BMI with other patient-specific factors into personalized immunotherapy strategies highlights the importance of tailored approaches to improve patient care and clinical outcomes.

Keywords:  body mass index; immune checkpoint inhibitors; non-small cell lung cancer; overall survival; progression-free survival

DOI:  https://doi.org/10.3390/cancers17071149
Am J Physiol Cell Physiol. 2025 Apr 18.

INFLAMMATION IN CANCER CACHEXIA: STILL THE CENTRAL TENET OR JUST ANOTHER PLAYER?

Noemi Iaia, Chiara Noviello, Maurizio Muscaritoli, Paola Costelli.

  Cancer cachexia, a multifactorial syndrome characterised by body weight loss, muscle and adipose tissue wasting, affects cancer patients. Over time, the definition of cachexia has been modified, including inflammation as one of the main causal factors. Evidences have suggested that a range of pro-inflammatory mediators may be involved in the regulation of intracellular signalling, resulting in enhanced resting energy expenditure, metabolic changes, and muscle atrophy, all of which are typical features of cachexia. Physiologically speaking, however, inflammation is a response aimed at facing potentially damaging events. Along this line, its induction in the cancer hosts could be an attempt to restore the physiological homeostasis. Interesting observations have shown that cytokines such as interleukins 4 and 6 could improve muscle wasting, supporting the view that the same mediator may exert pro- or anti-inflammatory activity depending on the immune cells involved as well as on the tissue metabolic demand. In conclusion, whether inflammation is crucial to the occurrence of cachexia or just one contributor among others, is still unclear. Indeed, inflammation could trigger cachexia, but it could also be the response to alterations of energy and protein metabolism and hormonal homeostasis. Probably both aspects are true, supporting the view that inflammation could be a crucial issue or just another player. Whether the causative role prevails over the compensatory one likely depends on the tumour type and stage, on patient lifestyle, on the presence of comorbidities, on the response to anticancer treatments, paving the way to a holistic, personalized approach to cancer cachexia.

Keywords:  Cachexia; Cancer; Cytokines; Inflammation; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00808.2024
Biochim Biophys Acta Mol Basis Dis. 2025 Apr 16. pii: S0925-4439(25)00204-2. [Epub ahead of print] 167859

Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation.

Wenying Shan, Shao-Lin Zhang, Yehuda G Assaraf, Kin Yip Tam.

  KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation in vitro, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.

Keywords:  Cancer metabolism; Combination therapy; KRAS Q61H mutation; Small molecule inhibitors

DOI:  https://doi.org/10.1016/j.bbadis.2025.167859
Cell Death Dis. 2025 Apr 13. 16(1): 286

Addition of metformin to anti-PD-1/PD-L1 drugs activates anti-tumor immune response in peripheral immune cells of NSCLC patients.

Luisa Amato, Caterina De Rosa, Gaetano Di Guida, Filippo Sepe, Annalisa Ariano, Sara Capaldo, Faiz Ul Haq, Alessandra Di Liello, Concetta Tuccillo, Stefano Lucà, Renato Franco, Viviana De Rosa, Francesca Iommelli, Alberto Servetto, Fortunato Ciardiello, Carminia Maria Della Corte, Floriana Morgillo.

Immunotherapy has transformed the treatment landscape for non-small cell lung cancer (NSCLC), yet achieving lasting benefits remains a challenge. The resistance mechanisms to immunotherapy are complex, involving interactions between tumor cells and immune cells that are not fully understood. Metformin, an FDA-approved diabetes medication, shows promise in enhancing immunotherapy efficacy by boosting anti-tumor immune responses, although the underlying molecular pathways are still being investigated. This study utilized co-culture models of cancer and immune cells to explore the effects of combining metformin with anti-PD-1/PD-L1 therapies on the anti-tumor immune response in LKB1 mutant (LKB1mut) versus wild-type (LKB1wt) NSCLC cells, alongside peripheral blood immune cells from NSCLC patients. The transcriptomic profiles of LKB1mut and LKB1wt NSCLC cells were characterized via bulk RNA sequencing to understand gene expression changes induced by metformin. Patients with advanced-stage NSCLC provided peripheral blood mononuclear cells (PBMCs) for analysis. The study assessed metformin's impact both alone and in combination with anti-PD-1/PD-L1 agents on innate immune pathways. Results indicated that metformin activated the cGAS-STING pathway and interferons in PBMCs, enhancing their anti-tumor capabilities. Notably, immune cells treated with metformin and immunotherapy exhibited synergistic effects, significantly reducing colony formation in LKB1mut NSCLC cells. Additionally, monocytes from NSCLC patients showed decreased viability of NSCLC cells in co-culture, independent of LKB1 status, and shifted towards an anti-tumor M1 phenotype with combined treatment. These findings were supported by 3D co-culture models involving tumor spheroids and patient-derived organoids, highlighting a novel biological rationale for using metformin alongside immunotherapeutic agents to boost anti-tumor activity across various immune cell subsets derived from NSCLC patients.

DOI: https://doi.org/10.1038/s41419-025-07636-7
Sci Rep. 2025 Apr 16. 15(1): 13148

Hypoxia LUAD H1975 cell-derived exosomal miR-671-3p promotes angiogenesis via regulating KLF2-VEGFR2 axis.

Kun Liu, Yi Wang, Qisen Li, Yujue Wang, Jinrui Liu, Jintao Zhou, Feiyu Song, Zhongyi Cong, Zhe Wang, Ning Kong.

  For solid tumors, hypoxia is associated with disease aggressiveness and poor outcomes. In addition to undergoing broad intracellular molecular and metabolic adaptations, hypoxic tumor cells extensively communicate with their microenvironments to facilitate conditions favorable for their survival, growth, and metastasis. This communication is mediated by diverse secretory factors, including exosomes (extracellular vesicles of endosomal origin). Exosomal cargo is altered considerably by hypoxia, with significant impacts on tumor-cell communication with both local and distant microenvironments. Exosomes released by cancer cells influence the tumor environment to accelerate metastasis. While tumor-derived exosomes have been identified as a major driver of premetastatic niche formation at distant sites, this mechanism in lung adenocarcinoma (LUAD) remains unclear. We found that miR-671-3p in exosomes derived from H1975 under hypoxic conditions target Krüppel-like factor 2 (KLF2) to regulate VEGFR2 expression in endothelial cells to promote angiogenesis. In addition, miR-671-3p is expressed at high levels in circulating exosomes isolated from patients with LUAD. Our study suggests that exosome miR-671-3p is involved in the formation of premetastatic niche and may serve as a blood-based biomarker for LUAD metastasis.

Keywords:  Angiogenesis; Exosome; Hypoxia; LUAD; Premetastatic niche; miR-671-3p

DOI:  https://doi.org/10.1038/s41598-025-97488-0
Biochem Biophys Res Commun. 2025 Apr 05. pii: S0006-291X(25)00480-2. [Epub ahead of print]763 151766

Integrative metabolic profiling of hypothalamus and skeletal muscle in a mouse model of cancer cachexia.

Jae Yeon Choi, Ye Jin Kim, Jeong Seob Shin, EunBi Choi, Yuhyun Kim, Min Gwan Kim, Yang Tae Kim, Byong Seo Park, Jae Kwang Kim, Jae Geun Kim.

  Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive weight loss, muscle wasting, and systemic inflammation. Despite its clinical significance, the underlying mechanisms linking central and peripheral metabolic changes remain incompletely understood. In this study, we employed a murine model of cancer cachexia induced by intraperitoneal injection of Lewis lung carcinoma (LLC1) cells to investigate tissue-specific metabolic adaptations. Cachectic mice exhibited reduced food intake, body weight loss, impaired thermoregulation, and decreased energy expenditure. Metabolomic profiling of serum, skeletal muscle, and hypothalamus revealed distinct metabolic shifts, with increased fatty acid and ketone body utilization and altered amino acid metabolism. Notably, hypothalamic metabolite changes diverged from peripheral tissues, showing decreased neurotransmitter-related metabolites and enhanced lipid-based energy signatures. Gene expression analysis further confirmed upregulation of glycolysis- and lipid oxidation-related genes in both hypothalamus and muscle. These findings highlight coordinated yet compartmentalized metabolic remodeling in cancer cachexia and suggest that hypothalamic adaptations may play a central role in the systemic energy imbalance associated with cachexia progression.

Keywords:  Cancer cachexia; Energy metabolism; Hypothalamus; Metabolites; Muscle

DOI:  https://doi.org/10.1016/j.bbrc.2025.151766
Cancer Immunol Immunother. 2025 Apr 17. 74(6): 173

Clinical and dynamic circulating cytokines profile features of long-term progression-free survival benefit to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Jia-Yi Deng, Ming Gao, Xue Fan, Hong-Hong Yan, Wei-Chi Luo, Ming-Yi Yang, Xiao-Rong Yang, Zhi-Hong Chen, Chong-Rui Xu, Qing Zhou.

   BACKGROUND: Immune checkpoint inhibitors (ICIs) offer durable progression-free survival (PFS) benefit in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, the predictors of long-term PFS (LTPFS) remain unclear.
METHODS: Advanced NSCLC patients receiving first-line ICIs monotherapy at Guangdong Lung Cancer Institute between December 2017 and August 2022 were identified. Predictive value of different characteristics was evaluated in LTPFS (PFS ≥ 24 months) compared with short-term PFS (STPFS, PFS ≤ 3 months). Circulating cytokine levels were evaluated in paired peripheral blood samples collected before and after ICIs treatment.
RESULTS: Among 202 patients identified and 171 included (median follow-up: 41.0 months), 44 (25.7%) experienced LTPFS, associated with a 5-year overall survival (OS) rate of 81.2%. Squamous NSCLC, intermediate or poor lung immune prognostic index (LIPI) score, and liver metastases, were negatively associated with LTPFS. High tumor mutational burden (TMB, ≥ 10 mutations/megabase) was enriched in LTPFS compared to STPFS (P = 0.002). Patients with both high TMB and PD-L1 demonstrated the greatest survival benefit from first-line ICIs monotherapy (median PFS: 24.5 months, median OS: 67.0 months). Thirty-eight peripheral blood samples were collected before and after ICIs treatment from 10 patients with LTPFS and 9 with STPFS, which revealed increased CCL11 (P = 0.013) and decreased IL1RA (P = 0.001) and IL17A (P = 0.003) levels in LTPFS after ICIs treatment.
CONCLUSION: Distinct clinical characteristics, including TMB, PD-L1, pathologic subtypes, LIPI score, number of organs involved, metastatic sites, and dynamic circulating cytokines profile features, can distinguish NSCLC patients achieving LTPFS from those with STPFS following first-line ICIs monotherapy.

Keywords:  Cytokine; Immunotherapy; Long-term; Non-small cell lung cancer; Predictive; Survival

DOI:  https://doi.org/10.1007/s00262-025-03984-7