bims-miptne 2025-03-23 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–03–23
thirteen papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Cryo-EM structure of the brine shrimp mitochondrial ATP synthase suggests an inactivation mechanism for the ATP synthase leak channel.
CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis.
Mitochondrial permeability transition drives the expression, identification and validation of necrosis-related genes in prognostic risk models of hepatocellular carcinoma.
The Mechanisms and Implications of Cardiolipin in the Regulation of Cell Death.
Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition.
Characterization of immune landscape and prognostic value of IL-17-related signature in invasive breast cancer.
Comparative efficacy and safety of PD-1 versus PD-L1 inhibitors in breast cancer treatment: A systematic review and meta analysis.
Structures and mechanism of human mitochondrial pyruvate carrier.
Targeting "don't eat me" signal: breast cancer immunotherapy.
Mitochondria: An overview of their origin, genome, architecture, and dynamics.
ERG1A K+ channel increases intracellular calcium concentration through modulation of calsequestrin1 in C2C12 myotubes.
Upregulation of RIG-I is Critical for Responsiveness to IFN-α Plus Anti-PD-1 in Colorectal Cancer.
Increased primary breast tumor expression of CD73 is associated with development of bone metastases and is a potential biomarker for adjuvant bisphosphonate use.

Cell Death Differ. 2025 Mar 19.

Cryo-EM structure of the brine shrimp mitochondrial ATP synthase suggests an inactivation mechanism for the ATP synthase leak channel.

Amrendra Kumar, Juliana da Fonseca Rezende E Mello, Yangyu Wu, Daniel Morris, Ikram Mezghani, Erin Smith, Stephane Rombauts, Peter Bossier, Juno Krahn, Fred J Sigworth, Nelli Mnatsakanyan.

Mammalian mitochondria undergo Ca2+-induced and cyclosporinA (CsA)-regulated permeability transition (mPT) by activating the mitochondrial permeability transition pore (mPTP) situated in mitochondrial inner membranes. Ca2+-induced prolonged openings of mPTP under certain pathological conditions result in mitochondrial swelling and rupture of the outer membrane, leading to mitochondrial dysfunction and cell death. While the exact molecular composition and structure of mPTP remain unknown, mammalian ATP synthase was reported to form voltage and Ca2+-activated leak channels involved in mPT. Unlike in mammals, mitochondria of the crustacean Artemia franciscana have the ability to accumulate large amounts of Ca2+ without undergoing the mPT. Here, we performed structural and functional analysis of A. franciscana ATP synthase to study the molecular mechanism of mPTP inhibition in this organism. We found that the channel formed by the A. franciscana ATP synthase dwells predominantly in its inactive state and is insensitive to Ca2+, in contrast to porcine heart ATP synthase. Single-particle cryo-electron microscopy (cryo-EM) analysis revealed distinct structural features in A. franciscana ATP synthase compared with mammals. The stronger density of the e-subunit C-terminal region and its enhanced interaction with the c-ring were found in A. franciscana ATP synthase. These data suggest an inactivation mechanism of the ATP synthase leak channel and its possible contribution to the lack of mPT in this organism.

DOI: https://doi.org/10.1038/s41418-025-01476-w
Cell Death Dis. 2025 Mar 15. 16(1): 177

CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis.

Zhijie Wang, Haicong Wu, Xin Chang, Yihang Song, Yan Chen, Ziwei Yan, Lun Gu, Ruxi Pang, Tian Xia, Zixuan He, Zhaoshen Li, Shuling Wang, Yu Bai.

Mitochondrial dysfunction contributes to the pathogenesis of ulcerative colitis (UC). As a mitochondrial isozyme of creatine kinases, which control energy metabolism, CKMT1 is thought to be a critical molecule in biological processes. However, the specific role of CKMT1 in intestinal inflammation remains largely unknown. Here, we observed markedly decreased CKMT1 expression in the colon tissues of UC patients and dextran sodium sulfate (DSS)-induced colitis mice. We generated intestinal epithelial-specific CKMT1 knockout mice and demonstrated the key role of CKMT1 in mitochondrial homeostasis, intestinal epithelial barrier function, oxidative stress, and apoptosis. In the in vitro experiments, CKMT1 expression limited the activation of the intrinsic and extrinsic apoptotic pathways in IECs. Mechanistically, the loss of CKMT1 expression in IECs increased TNF-α-induced mitochondrial reactive oxygen species (ROS) generation via reverse electron transfer (RET). RET-ROS promoted mitochondrial permeability transition pore (mPTP) opening, ultimately resulting in cell apoptosis during intestinal inflammation. In conclusion, our data demonstrated that CKMT1 is important in maintaining intestinal homeostasis and mitochondrial function. This study provides a promising basis for future research and a potential therapeutic target for inflammatory bowel disease (IBD).

DOI: https://doi.org/10.1038/s41419-025-07504-4
Transl Cancer Res. 2025 Feb 28. 14(2): 1037-1052

Mitochondrial permeability transition drives the expression, identification and validation of necrosis-related genes in prognostic risk models of hepatocellular carcinoma.

Jiaxuan Jin, Mengyuan Wang, Yinuo Liu, Wei Li, Xuemei Zhang, Zhuoxin Cheng.

   Background: Hepatocellular carcinoma (HCC) is a prevalent malignant tumor, and the current treatment methods exhibit various limitations. In recent years, the role of mitochondrial permeability transition-driven necrosis-related genes (MPT-DNRGs) in the pathogenesis and progression of severe diseases, particularly tumors, has garnered significant attention. This study aimed to identify new targets and concepts for MPT-DNRG-targeted therapy in HCC.
Methods: In this study, we utilized HCC-related datasets and MPT-DNRGs to identify differentially expressed genes (DEGs) between HCC patients and control groups. By conducting a cross-analysis of the results of DEGs and MPT-DNRGs, we screened candidate genes. Subsequently, univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis methods were employed to identify prognostic genes, which were used to construct a risk model and calculate individual risk scores for HCC patients. Additionally, we performed univariate and multivariate Cox regression analyses to identify independent prognostic factors and constructed a column chart based on these factors to predict the survival probability of HCC patients. Furthermore, gene set enrichment analysis (GSEA), the immune microenvironment, chemotherapy drugs, and the expression of prognostic genes between the two groups were analyzed. Finally, the expression of these prognostic genes was further confirmed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) technology.
Results: In this study, we identified 8,515 DEGs between HCC and control samples. By performing intersection analysis between DEGs and MPT-DNRGs, we pinpointed 15 candidate genes. Subsequently, through univariate Cox regression and LASSO regression analysis, we identified six genes (LMNB2, LMNB1, BAK1, CASP7, LMNA, and AKT1) that were significantly associated with overall survival (OS) in patients. Based on the median risk score, we categorized HCC patients into high-risk and low-risk groups. Kaplan-Meier (KM) survival analysis results demonstrated a significant difference in OS between the two groups, which was further validated through additional assessment. Furthermore, we constructed a nomogram to predict the survival probability of HCC patients. Moreover, GSEA revealed a crucial correlation between these genes and HCC, and highlighted a close association between risk scores and regulatory T cells. We also identified four chemotherapy drugs related to HCC. Finally, in both the training and validation cohorts, LMNB2, LMNB1, and LMNA exhibited high expression levels in tumor samples. Further validation using RT-qPCR confirmed that the expression of all prognostic genes was significantly higher in HCC group compared to the control group.
Conclusions: This study explored six prognostic genes (LMNB2, LMNB1, BAK1, CASP7, LMNA and AKT1) associated with MPT-DNRGs in HCC, which provides a reference for further research on HCC.

Keywords:  Hepatocellular carcinoma (HCC); mitochondrial permeability transition-driven necrosis-related genes (MPT-DNRGs); nomogram; prognosis; risk model

DOI:  https://doi.org/10.21037/tcr-24-1442
Cell Biochem Funct. 2025 Mar;43(3): e70066

The Mechanisms and Implications of Cardiolipin in the Regulation of Cell Death.

Zhou-Zhou Li, Han-Xi Xiao, Jian-Jie Hu, Wei Xie, Zu-Xiu Wang, Yong-Ping Pan, Xu-Huan Li, Xue-Feng Yu.

  Cardiolipin (CL), an exclusive phospholipid, is predominantly found within the confines of the inner mitochondrial membrane, playing an indispensable role in the sustenance of mitochondrial operations and the regulation of cellular energy metabolism. The influence of CL on the pathways of cell death has garnered significant interest in recent scholarly discourse. This review delves into the multifaceted roles of CL across various modes of cell demise, encompassing apoptosis, autophagy, pyroptosis, ferroptosis, necrosis, and necroptosis. The discussion extends to the examination of CL's implications in a clinical context, particularly concerning cardiovascular maladies, neurological degeneration, and oncological conditions. Through an integrative analysis of contemporary research findings, the aim is to elucidate the intricate dynamics of CL's involvement in cell death phenomena. While acknowledging the inherent limitations and the hurdles faced by current research endeavors, the therapeutic potential of CL as a modulator of cell death pathways is nonetheless encouraging. Forthcoming investigations must surmount these obstacles, thereby uncovering the nuanced mechanisms and impacts of CL in the realm of cell death and associated pathologies, potentially paving the way for innovative clinical intervention strategies.

Keywords:  apoptosis; autophagy; cardiolipin; ferroptosis; necroptosis; necrosis; pyroptosis

DOI:  https://doi.org/10.1002/cbf.70066
Nat Commun. 2025 Mar 18. 16(1): 2641

Guanine nucleotide biosynthesis blockade impairs MLL complex formation and sensitizes leukemias to menin inhibition.

Xiangguo Shi, Minhua Li, Zian Liu, Jonathan Tiessen, Yuan Li, Jing Zhou, Yudan Zhu, Swetha Mahesula, Qing Ding, Lin Tan, Mengdie Feng, Yuki Kageyama, Yusuke Hara, Jacob J Tao, Xuan Luo, Kathryn A Patras, Philip L Lorenzi, Suming Huang, Alexandra M Stevens, Koichi Takahashi, Ghayas C Issa, Md Abul Hassan Samee, Michalis Agathocleous, Daisuke Nakada.

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding of the MLL-fusion complex is impaired, reducing the expression of MLL target genes. Inhibition of guanine nucleotide biosynthesis or rRNA transcription further suppresses MLLr AML when combined with a menin inhibitor. Our findings underscore the requirement of guanine nucleotide biosynthesis in maintaining the function of the LEDGF/menin/MLL-fusion complex and provide a rationale to target guanine nucleotide biosynthesis to sensitize MLLr leukemias to menin inhibitors.

DOI: https://doi.org/10.1038/s41467-025-57544-9
Transl Cancer Res. 2025 Feb 28. 14(2): 907-929

Characterization of immune landscape and prognostic value of IL-17-related signature in invasive breast cancer.

Wenge Dong, Xiaojie Gu, Jiejing Li, Zhigang Zhuang.

   Background: Recently, interleukin 17 (IL-17) has been found to play a critical role in the development of breast cancer. However, its prognostic significance in invasive breast cancer (IBC) remains unclear. This study aims to determine the role of IL-17-related signatures in IBC to identify novel therapeutic options.
Methods: IBC data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to identify IL-17-related prognostic genes. A predictive model was developed using TCGA data and validated using METABRIC data. The relationship between IL-17 scores and immune landscape, chemotherapy drug sensitivity [half maximal inhibitory concentration (IC50)], and immune checkpoint gene expression was analyzed. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to validate key gene expression in breast tumor and normal tissue samples.
Results: The predictive model identified core IL-17-related prognostic genes and successfully estimated the prognosis of IBC patients. The model's validity was confirmed using METABRIC data. Patients with high IL-17 scores had worse overall survival (OS) compared to those with low IL-17 scores. Low IL-17 scores were associated with higher immune checkpoint gene expression and predicted enhanced responses to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) therapies. Patients with low IL-17 scores exhibited a higher abundance of immune microenvironment components. Furthermore, qRT-PCR confirmed the lower expression of OR51E1, NDRG2, RGS2, and TSPAN7 in breast tumors compared to normal tissue.
Conclusions: IL-17-related signatures are promising biomarkers for predicting the prognosis of IBC patients. These findings suggest that IL-17-related markers could be used to guide individualized therapeutic strategies, potentially improving outcomes for IBC patients.

Keywords:  Interleukin 17 (IL-17); immune microenvironment; invasive breast cancer (IBC); prognostic biomarkers

DOI:  https://doi.org/10.21037/tcr-24-1632
Int J Cancer. 2025 May 15. 156(10): 1936-1949

Comparative efficacy and safety of PD-1 versus PD-L1 inhibitors in breast cancer treatment: A systematic review and meta analysis.

Xintong Xie, Lingzhu Chen, Xiangyi Kong, Yujia Huo, Weiyuan Huang, Junjie Huang, Lin Zhang, Hongnan Jiang, Jidong Gao.

  The comparative efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitors versus programmed death protein 1 (PD-1) inhibitors in breast cancer treatment remain inconclusive, as no head-to-head randomized controlled trials (RCTs) conducted. This study aims to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy or in combination with chemotherapy for breast cancer. A systematic review and meta-analysis were performed using major databases and oncology conference proceedings. The primary outcomes were overall survival (OS) for advanced breast cancer and pathological complete response (PCR) rate for early breast cancer. Secondary outcomes included progression-free survival (PFS) for advanced breast cancer and incidence of adverse events (AEs). Seventeen studies met the inclusion criteria, consisting of seven RCTs on early-stage and 10 on advanced breast cancer. For advanced breast cancer, PD-1/PD-L1 inhibitors modestly improved OS compared to chemotherapy, with no significant differences between PD-1 and PD-L1 inhibitors. PD-L1 inhibitors showed greater improvement in PFS compared to PD-1 inhibitors. The likelihood of AEs of any grade was higher with PD-L1 inhibitor treatment than with PD-1 inhibitor treatment. In early breast cancer, combining PD-1/PD-L1 inhibitors with chemotherapy inducing higher PCR rates than chemotherapy alone, with PD-1 inhibitors achieving better outcomes than PD-L1 inhibitors. PD-1 inhibitors were linked to slightly higher rates of grade >2 AEs compared to PD-L1 inhibitors. The findings indicate that PD-1 inhibitors may offer advantages for advanced breast cancer due to similar OS and a lower rate of AEs. For early breast cancer, PD-1 inhibitors are recommended given their superior PCR rates.

Keywords:  PD‐1 inhibitor; PD‐L1 inhibitor; breast cancer; efficacy; safety

DOI:  https://doi.org/10.1002/ijc.35313
Nature. 2025 Mar 18.

Structures and mechanism of human mitochondrial pyruvate carrier.

Jiaming Liang, Junhui Shi, Ailong Song, Meihua Lu, Kairan Zhang, Meng Xu, Gaoxingyu Huang, Peilong Lu, Xudong Wu, Dan Ma.

Mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex essential for uptake of pyruvate into matrix as the primary carbon source for tricarboxylic acid (TCA) cycle1,2. Here, we report six cryo-EM structures of human MPC in three different states: three structures obtained at different conditions in intermembrane space (IMS)-open state with highest resolution of 3.2 Å, a structure of pyruvate-treated MPC in occluded state at 3.7 Å, and two structures in matrix-facing state bound with the inhibitor UK5099 or an inhibitory nanobody on the matrix side at 3.2 Å and 3.0 Å, respectively. MPC is assigned into a heterodimer consisting of MPC1 and MPC2, with the transmembrane domain adopting pseudo-C2-symmetry. Approximate rigid body movements occur between the IMS-open state and the occluded state, while structural changes primarily on the matrix side facilitate the transition between the occluded state and the matrix-facing state, revealing the alternating access mechanism during pyruvate transport. In the UK5099-bound structure, the inhibitor fits well and interacts extensively with a pocket that opens to the matrix side. Our findings provide important insights into the mechanisms underlying MPC-mediated substrate transport, and the recognition and inhibition by UK5099, which will facilitate future drug development targeting MPC.

DOI: https://doi.org/10.1038/s41586-025-08873-8
Breast Cancer Res Treat. 2025 Mar 18.

Targeting "don't eat me" signal: breast cancer immunotherapy.

Yue Gao, Xiaoyan Zhang, Mingqiang Ding, Zhenkun Fu, Lei Zhong.

   PURPOSE: Breast cancer ranks as the most prevalent cancer type impacting women globally, both in terms of incidence and mortality rates, making it a major health concern for females. There's an urgent requirement to delve into new cancer treatment methods to improve patient survival rates.
METHODS: Immunotherapy has gained recognition as a promising area of research in the treatment of breast cancer, with targeted immune checkpoint therapies demonstrating the potential to yield sustained clinical responses and improve overall survival rates. Presently, the predominant immune checkpoints identified on breast cancer cells include CD47, CD24, PD-L1, MHC-I, and STC-1, among others. Nevertheless, the specific roles of these various immune checkpoints in breast carcinogenesis, metastasis, and immune evasion have yet to be comprehensively elucidated. We conducted a comprehensive review of the existing literature pertaining to breast cancer and immune checkpoint inhibitors, providing a summary of findings and an outlook on future research directions.
RESULTS: This article reviews the advancements in research concerning each immune checkpoint in breast cancer and their contributions to immune evasion, while also synthesizing immunotherapy strategies informed by these mechanisms. Furthermore, it anticipates future research priorities, thereby providing a theoretical foundation to guide immunotherapy as a potential interventional approach for breast cancer treatment.
CONCLUSION: Knowledge of immune checkpoints will drive the creation of novel cancer therapies, and future breast cancer research will increasingly emphasize personalized treatments tailored to patients' specific tumor characteristics.

Keywords:  Breast cancer; Don’t eat me signal; Immunotherapy; Rare immune checkpoint

DOI:  https://doi.org/10.1007/s10549-025-07659-w
Biochim Biophys Acta Mol Basis Dis. 2025 Mar 19. pii: S0925-4439(25)00148-6. [Epub ahead of print] 167803

Mitochondria: An overview of their origin, genome, architecture, and dynamics.

João P Moura, Paulo J Oliveira, Ana M Urbano.

  Mitochondria are traditionally viewed as the powerhouses of most eukaryotic cells, i.e., the main providers of the metabolic energy required to maintain their viability and function. However, the role of these ubiquitous intracellular organelles far extends energy generation, encompassing a large suite of functions, which they can adjust to changing physiological conditions. These functions rely on a sophisticated membrane system and complex molecular machineries, most of which imported from the cytosol through intricate transport systems. In turn, mitochondrial plasticity is rooted on mitochondrial biogenesis, mitophagy, fusion, fission, and movement. Dealing with all these aspects and terminology can be daunting for newcomers to the field of mitochondria, even for those with a background in biological sciences. The aim of the present educational article, which is part of a special issue entitled "Mitochondria in aging, cancer and cell death", is to present these organelles in a simple and concise way. Complex molecular mechanisms are deliberately omitted, as their inclusion would defeat the stated purpose of the article. Also, considering the wide scope of the article, coverage of each topic is necessarily limited, with the reader directed to excellent reviews, in which the different topics are discussed in greater depth than is possible here. In addition, the multiple cell type-specific genotypic and phenotypic differences between mitochondria are largely ignored, focusing instead on the characteristics shared by most of them, with an emphasis on mitochondria from higher eukaryotes. Also ignored are highly degenerate mitochondrion-related organelles, found in various anaerobic microbial eukaryotes lacking canonical mitochondria.

Keywords:  Educational article; Mitochondrial endosymbiosis; Mitochondrial function; Mitochondrial morphology; Mitochondrial plasticity and dynamics; mtDNA

DOI:  https://doi.org/10.1016/j.bbadis.2025.167803
Sci Rep. 2025 Mar 19. 15(1): 9480

ERG1A K+ channel increases intracellular calcium concentration through modulation of calsequestrin1 in C2C12 myotubes.

Gregory H Hockerman, Evan Pratt, Shalini Guha, Emily LaVigne, Clayton Whitmore, Omar Khader, Natalie McClure, Sandra Zampieri, Jennifer Koran, W-H Wang, Amber L Pond.

  The ERG1A K+ channel modulates the protein degradation that contributes to skeletal muscle atrophy by increasing intracellular calcium concentration ([Ca2+]i) and enhancing calpain activity, but the mechanism by which the channel regulates the [Ca2+]i is not known. Here, we have investigated the effect of human ERG1A (HERG) on [Ca2+]i in C2C12 myotubes, using Fura-2 calcium assays, immunoblot, RT-qPCR, and electrophysiology. The data show that the rise in [Ca2+]i induced by KCl-stimulated depolarization is of greater amplitude in C2C12 myotubes over-expressing HERG relative to controls, but this difference does not result from an increase in L-type channel (Cav1.1) Ca2+ influx because there is no statistical difference in the nifedipine-sensitive response upon depolarization between the expression groups. Indeed, HERG overexpression in C2C12 myotubes has no effect on the amplitude of L-type channel current nor does it affect the mRNA levels nor protein abundance of the Cav1.1 channel. This finding suggests that HERG modulates excitation coupled calcium entry (ECCE). Indeed, the HERG-enhanced increase in [Ca2+]i induced by depolarization is blocked by 2-aminoethoxydiphenyl borate, an inhibitor of ECCE. Further, HERG also modulates the activity of ryanodine receptors (RYR1, a component of ECCE) as well as store operated calcium entry (SOCE). Therefore, we investigated the effect of HERG on calsequestrin1, a calcium buffering/binding protein known to modulate RYR1 and SOCE activities. Indeed, we find that calsequestrin1 mRNA levels are decreased 0.83-fold (p < 0.05) and the total protein abundance is lowered 77% (p < 0.05) in myotubes over-expressing HERG relative to controls. In conclusion, the data show that ERG1A overexpression modulates [Ca2+]i in skeletal muscle cells by lowering the abundance of the calcium buffering/binding protein calsequestrin1 which interacts with RyR1 and SOCE pathways. Indeed, we report that overexpression of HERG in myotubes increases [Ca2+]i by modulation of RyR1 as well as ECCE and SOCE activities. It is likely that HERG enhancement of RyR1 activity, through decreased Casq1 abundance, is increasing [Ca2+]i. This study provides a potential mechanism to explain how upregulation of ERG1A contributes to increased [Ca2+]i and, thus, atrophy in skeletal muscle.

Keywords:  Ether-a-gogo related K+ channel; Intracellular calcium; RyR1; Skeletal muscle; Store operated calcium entry; calsequestrin1

DOI:  https://doi.org/10.1038/s41598-025-93788-7
Cancer Med. 2025 Mar;14(6): e70802

Upregulation of RIG-I is Critical for Responsiveness to IFN-α Plus Anti-PD-1 in Colorectal Cancer.

Haihang Nie, Shilin Fang, Rui Zhou, Yifan Jia, Jingkai Zhou, Yumei Ning, Yali Yu, Yuntian Hong, Fei Xu, Qiu Zhao, Jiayan Nie, Fan Wang.

   BACKGROUNDS: Immunotherapy is a promising and effective approach that has achieved significant curative effects in colorectal cancer (CRC). Recently, retinoic acid-inducible gene I (RIG-I) has been shown to play a critical role in tumor immunity. However, the correlation between RIG-I and immunotherapy in CRC remains unclear.
METHODS: RIG-I expression was measured in CRC and normal samples based on analysis of the public databases, a tissue microarray, and CRC cell lines. The correlation between RIG-I and immune microenvironment was explored using well-established biological algorithms and in vitro and in vivo experiments.
RESULTS: We discovered that RIG-I expression was downregulated in CRC compared with normal samples. The bioinformatic algorithms indicated that high RIG-I-expressing samples showed a positive correlation with IFN-α response and enrichment of antitumor immune cells, especially CD8+ T cells. Furthermore, knockdown of RIG-I expression efficiently reduced the cell death, STAT1 phosphorylation, and CXCL10/11 expression induced by IFN-α in CRC cells. Finally, an in vivo study showed that the infiltration of CD3+ CD8+ T cells was significantly decreased in the RIG-I knockout group. An animal model further confirmed that the inhibition of tumor growth induced by IFN-α plus anti-PD-1 therapy was dependent on RIG-I expression.
CONCLUSION: RIG-I is a promising biomarker for CRC immunotherapy, which provides a novel concept for combinatorial immunotherapy.

Keywords:  RIG‐I; anti‐PD‐1; bioinformatic analysis; colorectal cancer; combinatorial immunotherapy; interferon‐α

DOI:  https://doi.org/10.1002/cam4.70802
Sci Rep. 2025 Mar 19. 15(1): 9449

Increased primary breast tumor expression of CD73 is associated with development of bone metastases and is a potential biomarker for adjuvant bisphosphonate use.

Nataliia Petruk, Steven L Wood, Walter Gregory, Ana Lopez-Guajardo, Maria Oliva, Mikko Mella, Jouko Sandholm, Arja Jukkola, Janet E Brown, Katri S Selander.

   PURPOSE: Increased CD73 expression has been associated with progression in various cancer types. Results of the AZURE and other trials suggest that, in postmenopausal breast cancer patients, adjuvant bisphosphonates inhibit bone relapses and prolong overall survival. Based on these findings, adjuvant bisphosphonates (typically zoledronic acid) are standard-of-care in postmenopausal patients with high-risk early breast cancer. However, biomarkers are needed for improved patient selection. The aim of this study was to investigate the association of primary tumor CD73 expression with later development of bone metastases.
METHODS: To determine whether CD73 levels correlated with tumor parameters (hormone receptor status, tumor stage and grade), patient outcomes (bone metastases and survival) or other patient characteristics (menopausal status, chemotherapy or statin use), we analyzed primary breast tumor CD73 expression immunohistochemically in tumor microarray samples from the AZURE (BIG01/04) trial.
RESULTS: In the AZURE control arm, high CD73 score are significantly prognostic for overall survival (p-value = 0.03, HR = 1.87, 95% CI = 1.06-3.29), disease-free survival (p-value = 0.06, HR = 1.66, 95% CI = 0.982-2.8) and time to first metastasis to bone (p-value = 0.04, HR = 2.23, 95% CI = 1.04-4.81), as compared with low CD73 scores. However, high CD73 score did not display an association with time to non-bone metastasis or first recurrence to a non-skeletal site. In the zoledronate arm, high CD73 score did not have association with patient outcomes, first metastasis to bone, nor with bone recurrence at any time (distant recurrence, including skeletal) or first non-skeletal recurrence. In multivariate testing, CD73 had no significant association with age, ER status, tumor stage, histological grade, menopausal status, chemotherapy or statin use in either arm.
CONCLUSIONS: High CD73 expression is associated with development of bone metastases. Zoledronate counteracts this effect. These results suggest that CD73 expression might serve as a biomarker for adjuvant zoledronic acid use.

Keywords:  Bone metastases; Breast cancer; CD73; TMA

DOI:  https://doi.org/10.1038/s41598-025-92841-9