bims-miptne 2025-04-06 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–04–06
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Peripheral inflammatory factors as prognostic predictors for first-line PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer.
Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.
Molecular mechanisms underlying TXNIP's anti-tumor role in breast cancer, including interaction with a novel, pro-tumor partner: CAST.
PD-L1 importance in malignancies comprehensive insights into the role of PD-L1 in malignancies: from molecular mechanisms to therapeutic opportunities.
Navigating established and emerging biomarkers for immune checkpoint inhibitor therapy.
Programmed Cell Death 10 (PDCD10) Is a Candidate Tumor-associated Gene in Esophageal Squamous Cell Carcinoma.
Phenotypes and cytokines of NK cells in triple-negative breast cancer resistant to checkpoint blockade immunotherapy.
Clinicopathological characteristics and the relationship of PD-L1 status, tumor mutation burden, and microsatellite instability in patients with esophageal carcinoma.
Metal ions and nanomaterials for targeted bone cancer immunotherapy.

Sci Rep. 2025 Apr 02. 15(1): 11206

Peripheral inflammatory factors as prognostic predictors for first-line PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer.

Chen-Xing Jin, Yan-Song Liu, He-Nan Qin, Yi-Bin Teng, Rui Sun, Zhong-Jing Ma, A-Man Wang, Ji-Wei Liu.

  Immune checkpoint inhibitors (ICIs) have significantly improved the efficacy and prognosis of patients with non-small cell lung cancer (NSCLC). However, there remains a lack of optimal predictive biomarkers for assessing the response of ICIs. This study aimed to evaluate peripheral inflammatory factors as potential predictive biomarkers for NSCLC patients treated with ICIs. We retrospectively analyzed the correlation between peripheral inflammatory factors and the efficacy and prognosis of 124 patients with driver gene-negative advanced NSCLC who received first-line ICIs at our center from September 2018 to June 2022. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. The association between the factors and multiple endpoints were investigated using univariate and multivariate analyses. A total of 124 patients were enrolled in this study. The objective response rate (ORR) was 49.2% and the disease control rate (DCR) was 97.6%, respectively. The median PFS was 12.7 months. The ORR differed statistically between groups based on the NLR, SII, with higher ORR observed in patients with an NLR ratio < 0.68, SII at 6 weeks < 531.26, and SII ratio < 0.74 (p < 0.05). The univariate analysis indicated that ECOG 0-1, smoking, NLR at 6 weeks < 2.72, NLR ratio < 0.68, LMR < 1.34, LMR ratio ≥ 1.38, and SII at 6 weeks < 531.26 were associated with longer PFS (p < 0.05). The multivariate analysis revealed that smoking (p = 0.013), baseline LMR (p = 0.015), and SII at 6 weeks (p = 0.010) were independent predictors of PFS. NLR, LMR, and SII maybe biomarkers for predicting the efficacy and prognosis of first-line ICIs therapy in driver gene-negative advanced NSCLC.

Keywords:  Biomarkers; Immune checkpoint inhibitors; Immunotherapy respond; Neutrophil to lymphocyte ratio; Non-small cell lung cancer; Systemic inflammatory index

DOI:  https://doi.org/10.1038/s41598-024-84469-y
FEBS J. 2025 Apr 02.

Protein succinylome analysis identifies citrate synthase as a central regulator of osteoclast metabolic activity.

Dayoung Yu, Yue Gao, Marcin Luzarowski, Elisabeth Seebach, Thomas Heitkamp, Michael Börsch, Thomas Ruppert, Katharina F Kubatzky.

  Tumour necrosis factor ligand superfamily member 11 (TNFSF11; RANKL) and macrophage colony-stimulating factor 1 receptor (M-CSF) differentiate macrophages into osteoclasts. This process is characterised by changes in metabolic activity that support energy-consuming processes. Treatment with RANKL triggers a phenotype of accelerated metabolism with enhanced glycolysis and an initial disruption of the tricarboxylic acid cycle (TCA) through increased expression of the enzyme aconitate decarboxylase (ACOD1), which results in an upregulation of intracellular succinate levels. Succinate then causes post-translational succinylation of lysine residues. ACOD1 as an inducer of protein succinylation and the desuccinylase NAD-dependent protein deacylase sirtuin-5, mitochondrial (SIRT5) are regulated differentially, and the initially high expression of ACOD1 decreases towards the end of differentiation, whereas SIRT5 levels increase. To mimic the effect of protein succinylation, diethyl succinate or a SIRT5 inhibitor was added during differentiation, which reduced the formation of large osteoclasts, showing its relevance for osteoclastogenesis. To identify succinylated proteins, we used an immunoaffinity-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach. Most lysine succinylated proteins were mitochondrial metabolic enzymes. Citrate synthase (CS), the enzyme catalysing the first reaction of the TCA cycle, showed a notable difference in succinylation levels before and after RANKL stimulation, with succinylation detected exclusively in stimulated cells. Immunoprecipitation assays confirmed CS succinylation. Using whole cell extracts, we observed that RANKL treatment decreased CS activity in a concentration-dependent manner. This suggests that CS could be critical in the context of energy production during osteoclastogenesis and that protein succinylation modulates the differentiation program of osteoclasts.

Keywords:  PTM scan; RANKL; citrate synthase; metabolism; mitochondria; osteoclast; post‐translational modification; succinylation

DOI:  https://doi.org/10.1111/febs.70090
Cell Death Dis. 2025 Apr 02. 16(1): 236

Molecular mechanisms underlying TXNIP's anti-tumor role in breast cancer, including interaction with a novel, pro-tumor partner: CAST.

Jasvinder Singh, Bindeshwar Sah, Yibin Deng, Robert Clarke, Liang Liu.

Thioredoxin-interacting protein (TXNIP) plays a pivotal role in glucose metabolism and redox signaling. Its emerging function as a potent suppressor of cell proliferation in various cancer contexts underscores its importance in cancer development. In a previous study, we found TXNIP activation by UNC0642, an inhibitor of histone methyltransferase G9A, significantly inhibited MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. Here, we demonstrated that TXNIP knockdown increased MDA-MB-231 tumor growth and metastasis in a mouse model. Reintroducing TXNIP into TXNIP-deficient HCC-1954 breast cancer cells decreased cell proliferation and migration while boosting the generation of reactive oxygen species, alongside reductions in mitochondrial respiration, mitochondrial membrane potential, and glycolysis. To elucidate the mechanisms underlying TXNIP's antitumor effects in breast cancer cells, we conducted co-immunoprecipitation and proteomic analyses that revealed calpastatin (CAST) as a novel TXNIP-interacting protein in MDA-MB-231 and HCC-1954 cells. Overexpression of CAST, an endogenous inhibitor of calpains, significantly increased xenograft tumor growth for both MDA-MB-231 and HCC-1954 cells, underscoring its novel role as a tumor promoter. In addition, we identified a positive correlation between the expression of TXNIP and interleukin-24 (IL-24), a molecule that induces cancer-specific apoptosis in several breast cancer cell lines. Our findings also show TXNIP's ability to decrease activation of STAT3, a key driver of oncogenesis. Finally, cells with high levels of TXNIP expression displayed increased susceptibility to IL-24 and WP1066, a specific STAT3 inhibitor, suggesting possible predictive value for TXNIP. Collectively, these findings unveil novel TXNIP-dependent pathways that may contribute to breast cancer pathogenesis, enriching our understanding of this molecule's intricate role in cancer and potentially paving the way for clinical translation.

DOI: https://doi.org/10.1038/s41419-025-07566-4
Clin Exp Med. 2025 Apr 03. 25(1): 106

PD-L1 importance in malignancies comprehensive insights into the role of PD-L1 in malignancies: from molecular mechanisms to therapeutic opportunities.

Mojdeh Soltani, Mohammad Abbaszadeh, Hamed Fouladseresht, Mark J M Sullman, Nahid Eskandari.

  The phenomenon of upregulated programmed death-ligand 1 (PD-L1) expression is common in numerous human malignancies. The overexpression of PD-L1 significantly contributes to immune evasion because its interaction with the PD-1 receptor on activated T lymphocytes impairs anti-tumour immunity by neutralizing T cell stimulatory signals. Furthermore, beyond its immunological interface, PD-L1 possesses intrinsic capabilities that directly modulate oncogenic processes, fostering cancer cell proliferation and survival. This dual function of PD-L1 challenges the efficacy of immune checkpoint inhibitors and highlights its possible application as a direct target for therapy. Recent discoveries concerning the cancer cell-intrinsic signalling pathways of PD-L1 have significantly enhanced our understanding of the pathological implications linked to its tumour-specific expression. These entail the orchestration of tumour proliferation and viability, maintenance of cancer stem cell-like phenotypes, modulation of immune responses, as well as impacts on DNA repair mechanisms and transcriptional regulation. This review aims to deliver an exhaustive synthesis of PD-L1's molecular underpinnings alongside its clinical implications in a spectrum of cancers, spanning both solid neoplasms and haematological disorders. It underscores the necessity for an integrated understanding of PD-L1 in further refining therapeutic strategies and improving patient outcomes.

Keywords:  Haematological malignancies; Immune checkpoints; Immunotherapy; PD-L1; Programmed death ligand-1; Solid tumour

DOI:  https://doi.org/10.1007/s10238-025-01641-y
Cancer Cell. 2025 Mar 27. pii: S1535-6108(25)00107-2. [Epub ahead of print]

Navigating established and emerging biomarkers for immune checkpoint inhibitor therapy.

Stephen L Wang, Timothy A Chan.

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.

DOI: https://doi.org/10.1016/j.ccell.2025.03.006
Anticancer Res. 2025 Apr;45(4): 1419-1433

Programmed Cell Death 10 (PDCD10) Is a Candidate Tumor-associated Gene in Esophageal Squamous Cell Carcinoma.

Yoshiki Hiraki, Takaaki Masuda, Yushi Motomura, Taro Tobo, Hideyuki Saito, Kosuke Hirose, Takashi Ofuchi, Yasuo Tsuda, Hajime Otsu, Yusuke Yonemura, Satohiro Kai, Masakazu Hirakawa, Kousei Ishigami, Koshi Mimori.

   BACKGROUND/AIM: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor survival rates. Effective molecular-targeted therapies are urgently needed. This study aimed to identify novel candidate tumor-associated genes in ESCC by analyzing chromosomal amplification regions.
MATERIALS AND METHODS: DNA copy number variation (CNV) and mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE). Single-cell RNA sequencing data from Gene Expression Omnibus (GEO) were analyzed using Scanpy. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded (FFPE) ESCC tissues. PDCD10 was identified as a potential tumor-associated gene, and its association with clinicopathological factors and prognostic impact was evaluated using Kaplan-Meier survival and Cox regression analyses. Pathway analysis was performed to investigate the biological processes, and drug sensitivity profiling was conducted to identify compounds whose efficacy correlated with PDCD10 expression in ESCC cell lines.
RESULTS: PDCD10, a signaling protein involved in cell proliferation and vascular development, showed significant amplification and over-expression in ESCC cases. High PDCD10 expression was associated with poor prognosis. Single-cell RNA sequencing confirmed its tumor-specific expression. GSEA revealed enrichment of mTORC1 signaling, E2F, and Myc target pathways in high PDCD10-expressing tumors. Drug sensitivity analysis identified Azelaic acid and Rebamipide as compounds whose efficacy correlated with PDCD10 expression in ESCC cell lines.
CONCLUSION: PDCD10 could be a novel tumor-associated gene associated with tumor progression and poor prognosis in ESCC. Azelaic acid and Rebamipide are candidate therapeutic agents targeting PDCD10.

Keywords:  PDCD10; chromosomal amplification; esophageal squamous cell carcinoma (ESCC); therapeutic target; tumor-associated gene

DOI:  https://doi.org/10.21873/anticanres.17527
Breast Cancer Res. 2025 Apr 03. 27(1): 51

Phenotypes and cytokines of NK cells in triple-negative breast cancer resistant to checkpoint blockade immunotherapy.

Youlong Wang, Yongluo Jiang, Fadian Ding, Jun Lu, Tong Huang, Guanqing Zhong, Pengfei Zhu, Yue Ma, Jin Li, Xinjia Wang, Jiacai Lin, Hongjun Zheng, Weidong Wang, Yiwei Xu, Xiajie Lyu, Yu Si Niu, Xin Qi, Jinjian Li, Bocen Chen, Tingting He, Jiling Zeng, Yifei Ma.

Neoadjuvant checkpoint blockade immunotherapy (NATI) significantly prolonged outcomes for triple-negative breast cancer (TNBC). Residual tumor cells that survive NATI represent high-risk cell populations with metastatic potential and usually evade immunosurveillance by NK cells. Using an 82-protein panel, we here profiled single-cell membrane proteomics of CD56+ (NCAM1+) NK cells from tumor, peri-cancerous tissue, as well as peripheral blood from 28 TNBC patients post-NATI of residual cancer burden II/III. Unsupervised clustering resulted in several distinct clusters: 2 tumor-infiltrating NK (TINK) clusters with divergent functions of immune activation (TNFRSF7+) and suppression (SELL+); 2 immuno-suppressive peri-cancerous clusters; and 1 periphery-specific cluster. Considering the contradiction of the 2 TINK clusters, we further tested cytokine functions of SELL + and TNFRSF7 + TINKs by single-cell secreting proteomics using a 32-cytokine panel. Consistently, SELL + TINK clusters were characterized by immuno-suppressive secretion patterns (IL10+). A low proportion of SELL + TINK cluster and low proportion of IL10 + secreting SELL + TINK cluster (single-cell secreting proteomics) were both associated with better progression-free survival time. These findings were validated in an independent cohort of 15 patients during 16-month follow-up. Overall, we identified a distinct immuno-suppressive TINK cell group, featuring IL10 + secreting and SELL expression with a strong relation to poor survival prognosis in TNBC patients post-NATI.

DOI: https://doi.org/10.1186/s13058-025-02003-y
BMC Cancer. 2025 Mar 31. 25(1): 576

Clinicopathological characteristics and the relationship of PD-L1 status, tumor mutation burden, and microsatellite instability in patients with esophageal carcinoma.

Suyao Li, Yongling Yu, Yirong Xu, Yue Zhou, Junxing Huang, Jinghao Jia.

   BACKGROUND: Despite significant advancements in the field of immunotherapy for esophageal cancer in recent years, only a minority of patients respond to these treatments, and effective predictive biomarkers remain elusive. Biomarkers such as programmed cell death 1 ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability (MSI) are pivotal in guiding immune checkpoint inhibitor therapies. This study aimed to explore the correlation between the three biomarkers in patients with esophageal carcinoma.
METHODS: We collected one hundred esophageal squamous cell carcinoma (ESCC) tumor samples from patients who have been undergoing radical resection of esophageal carcinoma. Each tissue sample was divided into two parts for next-generation sequencing (NGS) and immunohistochemical staining. Mutations were identified using the NGS database, and TMB was calculated. Multiplex PCR targeting five loci (NR21, NR24, NR27, BAT25, and BAT26) was used to evaluate MSI. PD-L1 expression was determined through immunohistochemical analysis.
RESULTS: Among the 100 ESCC patients, 54% (54/100) exhibited positive PD-L1 expression, 57% (57/100) demonstrated high TMB (TMB-H), and only 1% (1/100) had high MSI (MSI-H). Within the subset of TMB-H cases, 32 showed positive PD-L1 expression, with a single case displaying high expression of all three biomarkers, and 21 cases displaying low expression of all three biomarkers. There was no statistical association between PD-L1 expression levels and TMB. Further analysis showed a significant correlation between TNM staging and PD-L1 expression levels in ESCC tissues, with higher positive rates of PD-L1 expression observed in advanced stages. Similarly, a significant relationship was observed between TMB and lymph node metastasis.
CONCLUSIONS: Based on our preliminary results, TMB and PD-L1 can serve as potential early screening clinical biomarkers and molecular targets for immune treatment in ESCC. However, there is no apparent statistical association between TMB and PD-L1 expression levels. Furthermore, PD-L1 and TMB may independently influence the efficacy of immunotherapy, highlighting the inadequacy of single-marker detection in effectively predicting treatment outcomes.

Keywords:  Biomarkers; Esophageal squamous cell carcinoma; Immune checkpoint inhibitors; Immunotherapy; Programmed cell death 1 ligand 1; Tumor mutational burden

DOI:  https://doi.org/10.1186/s12885-025-13938-y
Front Immunol. 2025 ;16 1513834

Metal ions and nanomaterials for targeted bone cancer immunotherapy.

Sen Qin, YaoFeng Hu, HuaSong Luo, Wei Chu, RuCui Deng, JinLiang Ma.

  Bone cancer remains a significant challenge in oncology, with limited success in current therapeutic approaches, particularly immunotherapy. Emerging research highlights the potential of integrating metal ions and nanomaterials for targeted immunotherapy in bone cancer. Metal ions, including calcium, magnesium, and zinc, play a significant role in modulating immune responses within the tumor microenvironment, affecting essential pathways necessary for immune activation. Meanwhile, nanomaterials, particularly metallic nanoparticles, offer precise drug delivery and immune system modulation, improving the efficacy of immunotherapeutic agents. This review explores the synergistic effects of metal ion-nanomaterial conjugates, discussing their role in enhancing immune cell activation, particularly T-cells and macrophages, and their potential for controlled drug release. We highlight preclinical advancements in bone cancer treatment using metal ion-responsive nanoparticles, and address current challenges such as biocompatibility and toxicity. Finally, we discuss the future prospects of these technologies in personalized and precision medicine, aiming to revolutionize bone cancer immunotherapy.

Keywords:  bone cancer; immunotherapy and tumor microenvironment; metal ions; nanomaterials; osteosarcoma

DOI:  https://doi.org/10.3389/fimmu.2025.1513834