bims-meluca 2025-11-02 papers

Int J Cancer. 2025 Oct 26.

Prospective validation study of nutritional and immunological predictors in immune checkpoint inhibitor efficacy for non-small cell lung cancer.

Shinkichi Takamori, Mototsugu Shimokawa, Masafumi Yamaguchi, Masahide Mori, Shoichi Kuyama, Masahide Oki, Yoshifumi Nishimura, Katsumi Nakatomi, Hidetoshi Yanai, Noriaki Sukoh, Nobuo Hatakeyama, Toshiyuki Kita, Keiichi Fujiwara, Kenji Chibana, Masaki Okamoto, Mitsuhiro Takenoyama.

Immune checkpoint inhibitors (ICIs) have improved prognosis in non-small cell lung cancer (NSCLC). This prospective observational study aimed to validate the clinical impact of nutritional and immunological indices, including neutrophil-to-lymphocyte ratio (NLR), Glasgow prognostic score (GPS), prognostic nutritional index (PNI), controlling nutritional status (CONUT), and skeletal muscle area (SMA) in NSCLC patients treated with first-line ICIs. Three hundred and one patients with programmed cell death-ligand 1 (PD-L1) expression data were enrolled. SMA was measured using computed tomography images at the L3 level. Cut-off values were determined by our previous retrospective reports. The primary endpoint was progression-free survival (PFS). As a translational research, 15 myokines were evaluated from pre-treatment blood samples. The NLR, GPS, PNI, CONUT, and SMA were all significantly associated with PFS (p = .0128, p = .0016, p = .0046, p = .0485, and p = .0161, respectively). Multivariate analysis elucidated that age ≥75 years (p = .0256), male sex (p = .0227), combined chemotherapy (p = .0002), PD-L1 ≥50% (p = .0017), and SMA (p = .0354) were significant predictors of objective response. Multivariate analysis of PFS showed that performance status (p = .0104), PD-L1 (p <.0001), GPS (p = .0042), and SMA (p = .0367) were independent predictors. FSTL-1 was significantly lower in non-responders than in responders (p = .0212). In conclusion, the nutritional and immunological indices were validated to be significant predictors for the efficacy of ICIs. SMA was a predictor of both objective response and PFS, highlighting FSTL-1 as a potential biomarker for response to ICIs.

Keywords: immune checkpoint inhibitor; myokine; non‐small cell lung cancer; nutrition; sarcopenia

DOI: https://doi.org/10.1002/ijc.70170

Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00435-8. [Epub ahead of print]

Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.

Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo. These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies.

Keywords: CD147; MCT1; glucose stress; ketogenic diet; ketone metabolism; lung cancer; metabolic reprogramming; monocarboxylate transporter; tumor-initiating cells

DOI: https://doi.org/10.1016/j.cmet.2025.10.001

Clin Nutr ESPEN. 2025 Oct 29. pii: S2405-4577(25)02976-6. [Epub ahead of print]

Prognostic Utility of Cachexia in Lung Cancer: A Multicenter Cohort Analysis.

Lishuang Wei, Guotian Ruan, Heyang Zhang, Hanping Shi, Hailun Xie.

BACKGROUND: The clinical significance of the Asian Working Group on Cachexia (AWGC) criteria, as a novel diagnostic standard for cachexia, remains underexplored. This study aims to investigate the prognostic value of the AWGC criteria and to propose a scoring system for stratifying the severity of cachexia in lung cancer patients.
METHODS: Survival curves were generated using Kaplan-Meier analysis with log-rank tests. Cox proportional hazards models were employed for survival analysis, providing hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Logistic regression analysis was utilized to assess the independent association between cachexia and 90-day mortality, presenting the results as odds ratios (ORs) with 95% CIs.
RESULTS: This study enrolled a total of 3,424 lung cancer patients, comprising 86.6% with non-small cell lung cancer (NSCLC) and 13.4% with small cell lung cancer (SCLC). Patients with AWGC-defined cachexia had significantly poorer survival (55.8% vs. 39.3%, p < 0.001). Cachectic patients exhibited considerably worse survival rates in both SCLC (42.9% vs. 25.4%, p < 0.001) and NSCLC (57.8% vs. 41.4%, p < 0.001). Cox regression analysis indicated that AWGC-defined cachexia is an independent risk factor for survival in lung cancer patients (HR: 1.436, 95% CI: 1.306-1.580, p < 0.001). Moreover, AWGC-defined cachexia was significantly associated with poor prognosis in both SCLC (HR: 1.307, 95% CI: 1.007-1.698, p = 0.044) and NSCLC (HR: 1.377, 95% CI: 1.234-1.538, p < 0.001) patients. AWGC-defined cachexia was also found to be an independent risk factor for 90-day mortality in lung cancer patients (OR = 3.060, 95% CI: 2.254-4.155, p < 0.001). We developed a severity grading system for categorizing cachexia into Mild, Moderate, and Severe. Survival rates gradually decreased as the severity grading score increased (63.2% vs. 49.1% vs. 37.0% vs. 30.0%, p < 0.001).
CONCLUSIONS: AWGC-defined cachexia is an independent risk factor for both long-term prognosis and 90-day mortality in lung cancer patients.

Keywords: Asian Working Group for Cachexia criteria; Cancer cachexia; Lung cancer; Prognostic

DOI: https://doi.org/10.1016/j.clnesp.2025.10.017

In Vivo. 2025 Nov-Dec;39(6):39(6): 3278-3286

Simultaneous Investigation of sST2, IL-33, and Caspase-3 Serum Levels in Non-small Cell Lung Cancer.

Fatma Tuba Akdeniz, Zerrin Barut, Orçun Avşar, Sibel Arinç, Turgay Isbir.

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is a type of lung cancer with a high mortality rate. Many molecular and biochemical mechanisms are involved in its development, among which the suppression of tumorigenicity-2 protein (ST2) signaling pathway. Soluble ST2 (sST2) competes with transmembrane ST2 (ST2 ligand) for IL-33 binding. Activation of IL-33/ST2 pathway leads to M2 macrophage polarization, which promotes tumor progression. Since Caspase-3 is implicated in the regulation of IL-33 activity, the present study aimed to analyze the serum levels of IL-33, sST2, and caspase-3 in non-small cell lung cancer patients, compare them with control samples, and simultaneously investigate their predictive capacity.
MATERIALS AND METHODS: In this study, sST2 protein, IL-33, and caspase-3 levels were investigated using the ELISA method in serum samples collected from 25 patients diagnosed with non-small cell lung cancer and 25 completely healthy volunteer individuals. In the study, receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic power of the biomarkers.
RESULTS: Serum IL-33 levels were found to be significantly elevated in patients compared to the control group (p<0.0001). Similarly, the patient group showed significantly higher caspase-3 serum levels than the control group (p<0.030). While sST2 serum levels were higher in the patient group, the difference did not reach statistical significance. The ROC analysis for IL-33 showed an area under the curve (AUC) value of 0.838 [95% confidence interval (CI)=0.725-0.952, p<0.05], indicating that IL-33 is good diagnostic capability for NSCLC. The AUC value for Caspase-3 was 0.678 (95% CI=0.525-0.832, p=0.023), while for sST2, the AUC value was 0.499 (95% CI=0.333-0.665, p>0.05).
CONCLUSION: NSCLC patients are characterized by increased IL-33 and caspase-3 serum levels. These findings suggest that these markers could serve as valuable diagnostic and prognostic indicators, in addition to being potential therapeutic targets.

Keywords: IL-33; Non-small cell lung cancer; caspase-3; sST2 protein

DOI: https://doi.org/10.21873/invivo.14127