bims-meluca 2025-07-27 papers

Front Oncol. 2025 ;15 1628379

Cytokine profiling identifies circulating IL-2, IL23 and sPD-L1 as prognostic biomarkers for treatment outcomes in non-small cell lung cancer patients undergoing anti-PD1 therapy.

Kriti Jain, Anika Goel, Deepa Mehra, Deepak Kumar Rathore, Akshay Binayke, Shyam Aggarwal, Surajit Ganguly, Amit Awasthi, Evanka Madan, Nirmal Kumar Ganguly.

Background: This study investigates the predictive potential of circulating cytokines for response and survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) undergoing immune checkpoint inhibitor (ICI) therapy.
Materials and methods: A cohort of 64 patients with advanced NSCLC receiving ICI therapy were included. Baseline serum samples were collected prior to ICI initiation and profiled using a multiplex cytokine panel. Logistic regression, Cox regression, and Kaplan-Meier survival analysis were employed to assess associations between cytokine levels, therapeutic response, progression-free survival (PFS), and overall survival (OS). Gene expression levels of key cytokines were validated in peripheral blood mononuclear cells (PBMCs) of 17 patients (Responders = 7, Non-Responders = 10) and 3 Healthy Controls using quantitative real-time PCR.
Results: Elevated baseline levels of IL-2, IL-23, and sPD-L1 were significantly associated with clinical response to ICI therapy. Among these, sPD-L1 emerged as an independent predictor of response (AUC = 0.87). Multivariate Cox regression showed IL-2 (HR = 0.67), sPD-L1 (HR = 0.15), and IL-23 (HR = 1.18) were significantly associated with PFS and also predictive of OS. Notably, combined profiling of IL-2 and sPD-L1 enhanced predictive power (AUC = 0.95 for both PFS and OS). RT-PCR analysis of PBMCs corroborated these findings, confirming upregulation of IL-2 in responders and elevated IL-23 expression in non-responders.
Conclusion: Baseline cytokine profiling particularly of IL-2, sPD-L1, and IL-23 provides important prognostic and predictive information in advanced NSCLC patients undergoing ICI therapy. These biomarkers may facilitate more personalized approaches to immunotherapy and guide clinical decision-making.

Keywords: IL-2; IL-23; biomarkers; immune checkpoint inhibitors (ICIs); nivolumab; non-small cell lung cancer (NSCLC); sPD-L1

DOI: https://doi.org/10.3389/fonc.2025.1628379

Cell Death Discov. 2025 Jul 19. 11(1): 332

Activation of the integrated stress response and loss of cFLIPL under glutamine limitation induce IL-8 gene expression and secretion in glutamine-dependent tumor cells.

Rocío Mora-Molina, F Javier Fernández-Farrán, Abelardo López-Rivas, Carmen Palacios.

Growing evidence suggests that the proapoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) signaling pathway can also trigger the production of inflammatory cytokines, thereby promoting tumor progression. We recently reported that glutamine depletion impacts the survival of glutamine-dependent tumor cells by activating the TRAIL-R2/DR5-mediated apoptotic machinery. However, it remains unclear whether glutamine limitation activates a TRAIL-R2/DR5-regulated inflammatory response. In this study, we demonstrate that glutamine starvation activates two parallel signaling pathways, leading to the gene expression and secretion of the pro-angiogenic and pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells. Our findings reveal that the amino acid-sensing general control nonderepressible-2 kinase (GCN2)/activating transcription factor 4 (ATF4) signaling axis contributes to the upregulation of IL-8 gene expression in glutamine-deprived tumor cells. Furthermore, our results indicate that the loss of the long isoform of cellular FLICE-inhibitory protein (cFLIPL), which occurs as result of the metabolic stress induced by glutamine limitation, promotes TRAIL-independent activation of the NF-kB pathway via TRAIL-R2/DR5, a key mechanism driving the observed IL-8 upregulation under starvation conditions. Given the severe depletion of glutamine observed in growing tumors, our data suggest that IL-8 secretion, induced by this metabolic stress, may play a significant role in activating inflammatory and angiogenic responses, thereby counteracting apoptosis and ultimately promoting tumor progression.

DOI: https://doi.org/10.1038/s41420-025-02625-3

EMBO Mol Med. 2025 Jul 24.

De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma.

Duo Xu, Yanyun Gao, Shengchen Liu, Shiyuan Yin, Tong Hu, Haibin Deng, Tuo Zhang, Balazs Hegedüs, Thomas M Marti, Patrick Dorn, Shun-Qing Liang, Ralph A Schmid, Ren-Wang Peng, Yongqian Shu.

Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.

Keywords: De Novo Pyrimidine Synthesis; Metabolic Diversity; Neurofibromin 2 (NF2); Pleural Mesothelioma (PM); Synthetic Lethality

DOI: https://doi.org/10.1038/s44321-025-00278-4