bims-meluca 2026-05-17 papers

Biochem Soc Trans. 2026 May 27. 54(5): 547-559

Pro-inflammatory cytokine-driven molecular signaling in skeletal muscle during cancer cachexia.

Benudhara Pati, Nibedita Nandy, Birendra Kumar Bindhani, Naresh Chandra Bal.

Cancer cachexia is a multifactorial syndrome characterized by the progressive loss of muscle and fat, commonly observed among patients with cancer. It is very distinct from other skeletal muscle wasting such as sarcopenia and malnutrition and is known to reduce cancer treatment effectiveness. Cachexia progression is driven by a combination of factors, including hormonal dysregulation, anorexia, tumor-derived catabolic factors (in cancer cachexia), and systemic or muscular inflammation, all of which worsen overall muscle health. In this review, we will probe the role of pro-inflammatory cytokines, such as IL-6, IFN-γ, TNF-α, TGF-β, IL-1β, and IL-8, in driving the systemic inflammation and disruption of muscle metabolic homeostasis that support the development of cachexia. These cytokines may be produced from various organs, including the adipose depots that contribute to muscle wasting and metabolic dysfunction by disrupting the equilibrium between anabolic and catabolic processes. The ubiquitin-proteasome system, NF-κB, and JAK/STAT3 are important molecular pathways that mediate cytokine-induced catabolic signaling. The review further analyzes the context-dependent dual functions of these cytokines and the molecular mechanisms underlying the loss of their regulatory control during cancer progression. The limited success of current therapeutic approaches for cancer cachexia highlights the urgent need for evaluation of more targetable mechanisms for the treatments. Here, one of our main objectives is to probe whether suppression of pro-inflammatory cytokine signaling and activation of anti-inflammatory pathways can be utilized to modulate the tumor microenvironment, thereby countering cancer cachexia.

Keywords: Cancer cachexia; JAK/STAT3 pathway; Muscle wasting; NF-κB pathway; Pro-inflammatory cytokines; adipocytes

DOI: https://doi.org/10.1042/BST20260486

J Clin Invest. 2026 May 15. pii: e206031. [Epub ahead of print]136(10):

Liver-derived ceramides link metabolism to tissue wasting in cancer cachexia.

Kerui Huang, Norbert Perrimon, Marcus D Goncalves.

Cancer cachexia, characterized by weight loss, muscle wasting, and anorexia, complicates cancer treatment and adversely affects patient outcomes. Both tumor-derived and host inflammatory factors are implicated in aspects of cachexia. The search for circulating mediators of cancer cachexia has focused largely on secreted proteins, but metabolites may also drive systemic wasting. In this issue, Morigny, Rohm, and colleagues identified the liver as a major source of circulating ceramides in cachectic mice and patients with cancer and demonstrated that inhibiting ceramide synthesis attenuated muscle wasting and preserved function in cachectic mice. These findings position the liver as an endocrine organ in cachexia and introduce a druggable metabolic pathway with translational potential.

DOI: https://doi.org/10.1172/JCI206031

Analyst. 2026 May 11.

Quantitative metabolomics identifies prognostic biomarkers associated with NSCLC after chemoradiotherapy.

Leirui Yuan, Linfang Wu, Mingmin Qian, Chenxi Li, Daquan Wang, Xiang Fang, Shanlin Mao, Di Yang, Minghao Wang, Luhua Wang, Zeper Abliz, Nan Bi, Yanhua Chen.

Introduction: The high mortality of non-small cell lung cancer (NSCLC) is influenced by pre-treatment individual variability, yet reliable prognostic biomarkers are lacking, hindering precision therapy. Objectives: This study aimed to identify plasma metabolite biomarkers for predicting prognosis in stage III NSCLC patients using a targeted quantitative metabolomics approach. Methods: Plasma samples from 113 stage III NSCLC patients with long-term follow-up and 57 healthy controls were analyzed via LC-MS/MS-based targeted metabolomics. Patients were stratified into favorable and poor prognosis groups based on three-year survival. Differential metabolites were identified, and their association with overall survival was evaluated using Kaplan-Meier analysis. Results: Several metabolites differed between NSCLC patients and controls. Survival analysis revealed that elevated glutathione (GSH) levels were significantly associated with improved overall survival (p = 0.0013). Conversely, higher levels of glutamylglutamine (Glu-Gln) (p = 0.0117) and lysophosphatidylcholine 18:3 (LPC 18:3) (p = 0.0119) were correlated with poorer overall survival. Conclusion: This study identifies GSH and LPC 18:3 as promising prognostic biomarkers for stage III NSCLC. These findings provide new insights into patient stratification and the development of personalized treatment strategies.

DOI: https://doi.org/10.1039/d6an00069j

World J Oncol. 2026 Jun;17(3): 310-321

Incidence and Prognostic Value of TP53, STK11, and KEAP1 Mutations Between De Novo Versus Recurrent Actionable Mutation-Negative Non-Small Cell Lung Cancer: A Single-Center Retrospective Study.

Jorge Raul Vazquez-Urrutia, Natasha Venugopal, Junjia Zhu, Takefumi Komiya.

Background: In non-small cell lung cancer (NSCLC), mutations in TP53, STK11, and KEAP1 are common in tumors lacking actionable oncogenic drivers and have been associated with poor outcomes, though their prognostic impact remains context-dependent. We evaluated the incidence and prognostic significance of these mutations in actionable mutation-negative NSCLC, stratified by de novo versus recurrent disease.
Methods: We retrospectively analyzed 119 adult patients with NSCLC and available next-generation sequencing (NGS) results treated at our center through 2024. Cases with actionable mutations were excluded. Patients were classified as de novo (n = 82) or recurrent (n = 37) based on the disease status at the point of analysis. Between-group comparisons were done using Fisher's exact and Wilcoxon Rank-sum test. Overall survival and progression-free survival were assessed. All tests were two-sided and a P value < 0.05 was considered statistically significant.
Results: TP53 mutations were most frequent (61% de novo vs. 54% recurrent; P > 0.05). STK11 and KEAP1 mutations occurred at similar rates between groups (5-15%; P > 0.05). Baseline clinical characteristics were balanced. No significant differences in overall or progression-free survival were observed by mutational status in either cohort.
Conclusion: In this real-world cohort of actionable mutation-negative NSCLC cases, we did not detect significant prognostic associations for TP53, STK11, and KEAP1 mutations, and their incidence was similar between de novo and recurrent disease. These findings underscore the need for larger studies to evaluate the prognostic utility of these mutations in this clinical context.

Keywords: Actionable mutations; KEAP1; NGS; NSCLC; STK11; TP53

DOI: https://doi.org/10.14740/wjon2761

World J Surg Oncol. 2026 May 09.

Research progress on the biological function and molecular mechanism of GDF-15 in solid malignant tumors.

Dilinaer Aishanjiang, Yiliminuer Abulajiang, Reziya Saidula, Kaderya Abudusalam, Kadierjiang Musha.

Growth differentiation factor 15 (GDF-15), a stress-responsive member of the transforming growth factor-β (TGF-β) superfamily, is consistently upregulated in multiple solid tumors and closely linked to poor clinical outcomes. This review offers a systematic overview of the pleiotropic functions and principal signaling pathways of GDF-15 in solid malignancies. Within the tumor microenvironment (TME), GDF-15 fuels tumor progression by promoting proliferation, sustaining stemness, remodeling metabolism, and conferring therapy resistance via the TGF-β, Leukemia Inhibitory Factor (LIF)-Signal Transducer and Activator of Transcription 3 (STAT3), and AKT pathways. Notably, GDF-15 orchestrates an immunosuppressive TME by limiting T cell infiltration and expanding regulatory T cells, thereby facilitating immune evasion and resistance to immune checkpoint inhibitors (ICIs). Systemically, GDF-15 contributes to cancer cachexia through activation of the brainstem glial-cell-line-derived neurotrophic factor family receptor α-like (GFRAL)-rearranged during transfection (RET) receptor axis. Accumulating preclinical evidence positions GDF-15 as a promising therapeutic target, particularly for mitigating cachexia and potentiating immunotherapy. However, the context-dependent and dualistic nature of GDF-15 signaling, varying with tumor type, microenvironment, and disease stage, poses substantial hurdles for clinical translation. Future efforts should focus on deciphering the molecular determinants underlying GDF-15's functional duality, paving the way for precise, context-tailored intervention strategies.

Keywords: Cancer cachexia; GDF-15; Immune escape; Mitokine; Signaling pathway; TME; Therapeutic target

DOI: https://doi.org/10.1186/s12957-026-04341-3

J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70312

Targeting Cancer Cachexia: A Mechanistic Evaluation of Anti-GDF-15 Antibody-Based Combination Therapies.

Danna M Breen, Stephanie Joaquim, Brianna LaCarubba Paulhus, Donald Bennett, Barbara Bernardo, Susie Collins, Ryan M Esquejo, Ja Young Kim-Muller, Laura Lin, Matthew Peloquin, Zhidan Wu, Shuxi Qiao, John C Stansfield, Bei B Zhang, Michelle I Rossulek.

BACKGROUND: In a recent Phase 2 trial in patients with cancer cachexia, the anti-GDF-15 antibody ponsegromab resulted in increased body weight, appetite, muscle mass and physical activity. This study provides compelling evidence that targeting the GDF-15 pathway may offer a viable therapeutic strategy, while raising new mechanistic questions about how GDF-15 neutralization could be optimally integrated with other interventions to reverse the multifactorial cachexia syndrome. This series of experiments aimed to evaluate the effects of anti-GDF-15 antibody treatment in combination with muscle anabolic (anti-myostatin antibody) or appetite stimulant (ghrelin receptor agonist anamorelin) modulators using mouse cancer cachexia models.
METHODS: The effects of anti-GDF-15 monoclonal antibody alone and in combination with an anti-myostatin antibody or anamorelin fumarate were examined in GDF-15-dependent (HT-1080 and RENCA) and partially dependent (TOV21G) mouse tumour models. Comprehensive assessments included food intake, body weight, body composition (including fat, lean and muscle mass), muscle function and treadmill running. Circulating myostatin was measured in patient samples from an advanced NSCLC clinical study.
RESULTS: Anti-myostatin antibody treatment had limited efficacy in improving cachexia in mouse tumour models with high circulating GDF-15 (HT-1080 and RENCA), but improved cachexia (when combined with anti-GDF-15 antibody) in a tumour model with low circulating GDF-15 levels (TOV21G). In the TOV21G model, combining anti-myostatin and anti-GDF-15 antibodies led to even greater increases in body weight and hindlimb muscle mass compared with anti-GDF-15 antibody alone (p < 0.001 for muscle mass); however, the increase in muscle strength and treadmill running did not reach statistical significance over monotherapy. When anamorelin was combined with anti-GDF-15 antibody, body weight was elevated compared with the HT-1080 tumour-bearing vehicle group (p < 0.0001) but did not reach statistical significance over anti-GDF-15 antibody alone. Similar observations of the combination treatment were found for food intake, fat mass and gastrocnemius (p < 0.05). Circulating myostatin was negatively correlated with weight loss in patients with cancer (p < 0.01).
CONCLUSION: These data provide proof-of-principle that mechanistically distinct approaches targeting muscle anabolism and appetite may act additively with GDF-15 neutralization, particularly in cancer cachexia settings with lower GDF-15 dependence.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01360554.

Keywords: GDF‐15; cachexia; ghrelin; mouse tumour models; myostatin

DOI: https://doi.org/10.1002/jcsm.70312