bims-meluca 2026-08-16 papers

Transl Lung Cancer Res. 2026 Jul 31. 15(7): 206

Baseline IL-6, IL-8, IFN-ω, and perforin as prognostic biomarkers in immune checkpoint inhibitor-treated metastatic non-small cell lung cancer.

Varshini Odayar, Hyojung Jang, Ashley Pearson, Jadyn James, Emily Kloska, Benjamin H Singer, Shadia Jalal, Charles J Nock, Lili Zhao, Michael Green, Nithya Ramnath.

Background: Prognostic serum biomarkers of immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC) are sparse. We evaluated baseline cytokines as markers of outcomes in ICI-treated metastatic NSCLC.
Methods: Baseline serum cytokines were quantified in 96 patients with metastatic NSCLC receiving ICIs. Separate multivariable models were fit for progression-free survival (PFS) and overall survival (OS), adjusting for clinical covariates. Hazard ratios (HRs) were expressed per doubling in cytokine concentration. Significant cytokines were then incorporated into multivariable Cox models, and model discrimination was assessed using time-dependent area under the curve (AUC). Latent class analysis (LCA) was performed to identify cytokine-defined patient phenotypes associated with survival.
Results: Each doubling of interleukin-6 (IL-6) increased the hazard of death by 34% [HR =1.34; 95% confidence interval (CI): 1.13-1.60; P<0.001] and interleukin-8 (IL-8) by 36% (HR =1.36; 95% CI: 1.16-1.59; P<0.001). Conversely, each doubling of interferon-omega (IFN-ω) (HR =0.87; 95% CI: 0.80-0.95; P=0.001) and perforin (HR =0.50; 95% CI: 0.33-0.76; P<0.001) decreased mortality risk. Multivariable cytokine models incorporating IL-6, IL-8, IFN-ω, and perforin achieved time-dependent AUCs >0.70 for PFS and OS. LCA identified two cytokine classes: one enriched for IL-6/IL-8 (poor outcomes) and another enriched for IFN-ω/perforin (favorable outcomes).
Conclusions: Higher baseline serum IL-6 and IL-8 concentrations were associated with inferior survival, whereas higher baseline serum IFN-ω and perforin were associated with improved survival in ICI-treated metastatic NSCLC, defining distinct host immune-inflammatory phenotypes with prognostic relevance.

Keywords: Interleukin-6 (IL-6); immune checkpoint inhibitor (ICI); interferon-omega (IFN-ω); interleukin-8 (IL-8); perforin

DOI: https://doi.org/10.21037/tlcr-2026-0446

Clin Transl Med. 2026 Aug;16(8): e70741

Endogenous CD155 drives metabolic reprogramming via PI3K/AKT/HIF-1α-glycolysis axis to mediate anti-PD-1 resistance in non-small cell lung cancer.

Wei-Guang Du, Xi-Yang Tang, Yu-Long Zhou, Run-Ze Zhang, Zhi-Bo Feng, Meng-Chao Li, Jun-Yang Pan, Yao Lv, Xiao-Liang Xu, Xiao-Long Yan, Nan Ma, Jin-Bo Zhao.

OBJECTIVE: Anti-PD-1 therapy resistance remains a critical barrier in non-small cell lung cancer (NSCLC) management, and the underlying mechanisms are incompletely defined.
METHODS: We generated CD155‑knockout (KO) NSCLC cell lines using the CRISPR‑Cas9 system and performed systematic multi‑omics analyses, including single‑cell RNA‑seq, bulk RNA‑seq, proteomics, and metabolomics. The key molecular mechanisms were further validated by immunohistochemistry (IHC), western blotting, and chromatin immunoprecipitation (ChIP). Functional assays assessed cell proliferation, migration, and metabolic phenotypes, while the therapeutic efficacy was assessed in vivo using AAV9_shCD155.
RESULTS: Single-cell sequencing revealed aberrantly high CD155 expression in NSCLC patients with poor response to anti-PD-1 therapy. High CD155 expression in NSCLC tissues correlated with unfavourable prognosis. ETS1 was identified as a direct transcriptional driver of CD155. Multi-omics analysis and functional assays demonstrated that CD155 upregulates the expression of key glycolytic proteins (GLUT1, GLUT3, LDHB) by activating the PI3K/AKT/HIF-1α signalling axis, thereby driving glycolytic metabolism, proliferation, and migration of tumour cells. CD155 knockout significantly suppressed these malignant phenotypes. In xenograft mouse models, monotherapy with AAV9_shCD155 effectively inhibited tumour growth and postoperative recurrence. More importantly, in humanised mouse models, combining AAV9_shCD155 with pembrolizumab produced synergistic anti-tumour effects, more significantly suppressing tumour growth and promoting immune cell infiltration into the tumour microenvironment.
CONCLUSION: CD155 mediates anti-PD-1 resistance by activating PI3K/AKT/HIF-1α-driven glycolytic reprogramming. Targeting CD155 combined with anti-PD-1 overcomes resistance, supporting a dual-target therapeutic strategy.
KEY POINTS: CD155 is identified as a key driver of anti-PD-1 resistance in NSCLC. CD155 promotes tumour glycolysis and malignant progression via the PI3K/AKT/HIF-1α signalling axis. AAV9_shCD155 combined with anti-PD-1 markedly inhibits tumour growth and promotes immune infiltration.

Keywords: AAV9_shCD155; CD155; NSCLC; anti‐PD‐1 therapy; glycolysis; mechanism of resistance

DOI: https://doi.org/10.1002/ctm2.70741

Redox Biol. 2026 Aug 10. pii: S2213-2317(26)00345-9. [Epub ahead of print]96 104346

TDP-43 drives ferroptosis evasion by modulating PCBP1/PCBP2 axis to promote lung adenocarcinoma growth.

Bowen Liu, Xin Chen, Jingjing Chen, Jinyan Feng, Jin Wang, Xin Jin, Jinling Cao, Bingqian Zhao, Huilong Yin, Jingru Wang, Yun Yang, Pengfei Zheng, Shujun Ma, Wei Liao, Min Zhang, Bo Yang, Jie Wang, Xiaofang Geng, Haomin Cai.

Lung adenocarcinoma (LUAD) continues to be one of the top causes of cancer-associated deaths worldwide. TAR DNA-binding protein 43 (TDP-43) has been linked to several tumor-related biological processes, yet its specific role in LUAD growth remains poorly understood. Ferroptosis, an iron-dependent regulated cell death, is increasingly recognized as a key process affecting tumor development. Here, we report that TDP-43 acts as a key ferroptosis regulator facilitating LUAD growth. TDP-43 is upregulated in LUAD tissues and positively correlates with poor patient prognosis. Functionally, TDP-43 silencing impairs LUAD cell proliferation and promotes cell death, whereas TDP-43 overexpression exerts the opposite effects. Consistently, TDP-43 knockdown markedly suppresses xenograft tumor growth in vivo. Whole transcriptome sequencing combined with subsequent validation assays revealed that TDP-43 is capable of suppressing ferroptosis in LUAD cells. Accordingly, TDP-43 silencing sensitizes cells to erastin/RSL3-induced ferroptosis. Mechanistically, TDP-43 exerts its effects through two distinct pathways: it interacts with transcription factor VDR via its C-terminal domain to activate PCBP1 transcription, while directly binding to the UG-rich motif within the 3'UTR of PCBP2 mRNA to stabilize its transcript. Upregulation of iron chaperones PCBP1 and PCBP2 alleviates intracellular Fe2+ overload and lipid peroxidation, allowing LUAD cells to escape ferroptosis and support tumor growth. These results highlight TDP-43's pivotal role in regulating LUAD ferroptosis and offer promising directions for LUAD treatment.

Keywords: Ferroptosis; Lung adenocarcinoma; PCBP1; PCBP2; TDP-43

DOI: https://doi.org/10.1016/j.redox.2026.104346

Thorac Cancer. 2026 Aug;17(16): e70378

Diabetes Mellitus as an Independent Risk Factor for Unfavorable Prognosis in Patients With Small Cell Lung Cancer.

Rui Yan, Patiguli Yisilamu, Yang Ge, Weiwei Zhou.

BACKGROUND: Type 2 diabetes mellitus (DM) is implicated in cancer development and associated with poor survival in patients with cancer. However, the impact of DM on the outcome of small cell lung cancer (SCLC) remains unknown. This study investigated the correlation between DM and clinical outcomes and long-term prognosis of patients with extensive-stage small cell lung cancer (ES-SCLC).
METHODS: This retrospective cohort study was conducted using the medical records of patients with ES-SCLC treated with immune checkpoint inhibitors (ICIs) and chemotherapy. The demographic and clinical characteristics were retrospectively analyzed. Univariate and multivariate analyses were performed using Cox proportional hazards regression to evaluate the impact of the clinical characteristics on survival. Progression-free survival (PFS) and overall survival (OS) were compared between patients with or without DM.
RESULTS: Of the 91 patients with ES-SCLC, 32 were diagnosed with DM before ES-SCLC (35.2%). Patients with DM had significantly shorter median PFS (6 vs. 15 months, p = 0.026) and median OS (12 vs. 22 months, p = 0.013) than those without diabetes, despite receiving comparable chemoimmunotherapy. Multivariate cox regression analysis showed that DM was an independent risk factor for shorter mOS (HR 2.05, 95% CI 1.02-4.13, p = 0.044).
CONCLUSIONS: Patients with ES-SCLC and comorbid diabetes exhibited significantly shorter OS and PFS compared with those without diabetes. DM serves as an independent adverse prognostic risk factor for ES-SCLC.

Keywords: ES‐SCLC; chemotherapy; diabetes mellitus; immune checkpoint inhibitors

DOI: https://doi.org/10.1111/1759-7714.70378

Eur Geriatr Med. 2026 Aug 14.

Circulating biomarkers of the brain-muscle-metabolic axis in primary sarcopenia: neudesin, nesfatin-1, and irisin.

Gulru Ulugerger Avci, Seyda Bilgin, Yunus Avci, Gunay Can, Ibrahim Murat Bolayirli, Deniz Suna Erdincler, Alper Doventas.

PURPOSE: Sarcopenia is an age-related geriatric syndrome characterized by the progressive loss of skeletal muscle mass, strength, and physical performance. Although muscle-based assessments remain central to diagnosis, no specific circulating biomarker is currently available for early detection. Emerging evidence suggests that neudesin, nesfatin-1, and irisin are involved in muscle metabolism, energy homeostasis, and the regulation of inflammation. This study aimed to investigate the association of these biomarkers with primary sarcopenia in older adults and to evaluate their potential diagnostic utility.
METHODS: This study included 88 participants aged ≥ 65 years (58 women, 30 men), excluding secondary sarcopenia. Diagnosis was based on EWGSOP2 criteria. Serum neudesin, nesfatin-1, and irisin levels were measured by enzyme-linked immunosorbent assay (ELISA). Sociodemographic characteristics, comorbidities, medication use, anthropometric parameters, and comprehensive geriatric assessment data were collected.
RESULTS: Serum concentrations of neudesin, nesfatin-1, and irisin were significantly lower in individuals with sarcopenia compared to non-sarcopenic controls (p = 0.001, p < 0.001, and p < 0.001, respectively). After adjustment for body mass index (BMI), neudesin and nesfatin-1 remained independently associated with sarcopenia, whereas the association between irisin and sarcopenia was attenuated. All three biomarkers demonstrated good discriminatory ability for sarcopenia.
CONCLUSION: Reduced serum concentrations of neudesin, nesfatin-1, and irisin are significantly associated with primary sarcopenia in older adults. Nesfatin-1 and neudesin appear to be the most robust biomarker candidates, independent of adiposity. These results suggest that sarcopenia involves alterations in interconnected metabolic, endocrine, and neurotrophic pathways within the brain-muscle-metabolic axis. This study is the first to evaluate a combined neurotrophic, myokine, and metabolic biomarker panel in primary sarcopenia. Additional prospective studies are necessary to validate these findings and determine their clinical relevance.

Keywords: Irisin; Nesfatin-1; Neudesin; Older adults; Sarcopenia; Serum biomarkers

DOI: https://doi.org/10.1007/s41999-026-01582-z