bims-miptne 2025-03-30 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–03–30
twenty-two papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Cyclophilin D knockdown/knockout promotes microglia M2 polarization by inhibiting STAT1 to alleviate neuroinflammation in neonatal white matter injury.
Necroptosis in myocardial ischaemia-reperfusion injury: current update on mechanisms, therapeutic targets, and translational potential.
Multiple Inhibitory Mechanisms of DS16570511 Targeting Mitochondrial Calcium Uptake: Insights from Biochemical Analysis of Rat Liver Mitochondria.
Calcium channels as pharmacological targets for cancer therapy.
The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.
The role of calcium signaling in organotropic metastasis of cancer.
Crosstalk between calcium and reactive oxygen species signaling in cancer revisited.
Relative expression orderings based prediction of treatment response to Anti-PD-1 immunotherapy in advanced melanoma.
A New Perspective on the Role of Alterations in Mitochondrial Proteins Involved in ATP Synthesis and Mobilization in Cardiomyopathies.
CD8+CD28+PD1- T Cells as a Prognostic Biomarker in Endometrial Cancer.
High Expression of Calreticulin Affected the Tumor Microenvironment and Correlated With Worse Prognosis in Patients With Triple-Negative Breast Cancer.
Unraveling the Role of Tumor-infiltrating Immune Cells in Modulating Cancer Drug Resistance.
Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
Targeted STING Activation Using Modified Ultrasound-Responsive Microbubbles Enhances Immune Checkpoint Blockade Against Melanoma.
Targeting Ion Channels: Blockers Suppress Calcium Signals and Induce Cytotoxicity Across Medulloblastoma Cell Models.
Identification of autophagy-related immune targets for enhancing immunotherapy in pancreatic cancer aggressiveness.
PD-L1 blockade peptide-functionalized NaGdF4 nanodots for efficient magnetic resonance imaging-guided immunotherapy for breast cancer.
Therapeutic strategies for adrenocortical carcinoma: integrating genomic insights, molecular targeting, and immunotherapy.
A protease-cleavable liposome for co-delivery of anti-PD-L1 and doxorubicin for colon cancer therapy in mice.
Mitochondria targeted nanoparticles for the treatment of mitochondrial dysfunction-associated brain disorders.
Mycobacterium tuberculosis phagosome Ca2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages.
High Sugar Induced RCC2 Lactylation Drives Breast Cancer Tumorigenicity Through Upregulating MAD2L1.

Brain Res. 2025 Mar 23. pii: S0006-8993(25)00155-6. [Epub ahead of print] 149596

Cyclophilin D knockdown/knockout promotes microglia M2 polarization by inhibiting STAT1 to alleviate neuroinflammation in neonatal white matter injury.

Jiayu Zhou, Ting Gao, Wan Tang, Ziming Wang, Ling Zhao, Laishuan Wang.

  The activation of microglia cells is intimately associated with the pathophysiology of neuroinflammation and neonatal white matter injury (WMI). Cyclophilin D (CypD), a matrix cyclophilin, is known to be one of the important regulators of mitochondrial permeability transition pore. Currently, CypD has been discovered the function of regulating inflammation. However, its impact on microglia in the context of neonatal WMI remains unclear. In our study, CypD inhibition ameliorated microglia activation, decreased pro-inflammatory factor levels, and increased anti-inflammatory factor levels in both neonatal WMI mice and oxygen glucose deprivation/reperfusion (OGD/R)-induced BV2 microglial cells. CypD knockout promoted myelination and rescued neurological function in mice following hypoxic-ischemic injury. In addition, CypD knockdown alleviated mitochondrial dysfunction of BV2 microglial cells. RNA-Seq indicated that CypD inhibition downregulated STAT1. Western blotting results verified that CypD inhibition significantly downregulated the phosphorylation level of STAT1. Our research revealed the protective role of CypD inhibition in neuroinflammation and mitochondrial function of microglia. Targeting CypD expression in microglia may be a potential therapeutic option for neonatal WMI.

Keywords:  Cyclophilin D; Inflammation; Microglia; Mitochondria; Neonatal; White matter injury

DOI:  https://doi.org/10.1016/j.brainres.2025.149596
Apoptosis. 2025 Mar 27.

Necroptosis in myocardial ischaemia-reperfusion injury: current update on mechanisms, therapeutic targets, and translational potential.

Siarhei A Dabravolski, Vladislav A Kalmykov, Anastasia O Maksaeva, Ulyana V Rozhkova, Ksenia O Lapshina, Alexander N Orekhov.

  Necroptosis is a programmed form of cell death that has gained significant attention in the field of cardiovascular research due to its involvement in myocardial infarction (MI) and myocardial ischaemia-reperfusion (I/R) injury. Unlike apoptosis, necroptosis elicits a pro-inflammatory response, contributing to myocardial injury, fibrosis, and adverse remodelling. This review aims to provide an overview of the molecular mechanisms underlying necroptosis, with a particular focus on its role in myocardial I/R injury. Key regulatory proteins such as Receptor-interacting protein kinase 3 (RIPK3) and Mixed lineage kinase domain-like protein (MLKL) are central to the necroptotic process, mediating cell death and inflammation. The review discusses the potential of targeting necroptosis as a therapeutic strategy for managing cardiovascular diseases, particularly post-MI. The RIPK3-CaMKII-mitochondrial permeability transition pore (mPTP) pathway is identified as a critical signalling axis in necroptosis and its inhibition may offer protective benefits in myocardial injury. The review also considers the role of natural and chemical inhibitors and other genes in necroptosis regulation. Overall, targeting necroptosis represents a promising avenue for therapeutic intervention to mitigate cardiac injury, promote recovery, and improve long-term patient outcomes in cardiovascular diseases.

Keywords:  Cardiac damage; Ischaemia-reperfusion injury; Myocardial infarction; Necroptosis; RIPK3 inhibitors; RIPK3-MLKL pathway

DOI:  https://doi.org/10.1007/s10495-025-02108-x
Int J Mol Sci. 2025 Mar 16. pii: 2670. [Epub ahead of print]26(6):

Multiple Inhibitory Mechanisms of DS16570511 Targeting Mitochondrial Calcium Uptake: Insights from Biochemical Analysis of Rat Liver Mitochondria.

Akiko Yamada, Akira Watanabe, Atsushi Nara, Tsubasa Inokuma, Masatake Asano, Yasuo Shinohara, Takenori Yamamoto.

  Mitochondrial calcium (Ca2+) uptake plays a key role in mitochondrial physiology and disease development. This process is regulated by the mitochondrial calcium uniporter (MCU) complex. DS16570511 is a membrane-permeable drug that inhibits mitochondrial Ca2+ uptake, although its inhibitory mechanisms remain unclear. In this study, we evaluated the effects of DS16570511 on various mitochondrial functions through biochemical analyses. We found that DS16570511 affects multiple mitochondrial functions and exhibits variable potency in inhibiting individual processes. Specifically, DS16570511 not only inhibits MCU, its initially reported target, but also respiratory chain complexes and FoF1-adenosine triphosphatase/adenine nucleotide translocator, particularly respiratory chain complex II. Furthermore, the carboxyl group at the molecular terminus of DS16570511 plays a critical role in its inhibitory effects on mitochondrial Ca2+ uptake through respiratory chain complex II inhibition. These findings enhance our understanding of the mechanisms by which DS16570511 inhibits mitochondrial Ca2+ uptake and provide valuable insights for the clinical application of mitochondrial Ca2+ uptake inhibitors.

Keywords:  DS16570511; inhibitor; mitochondrial calcium uniporter; rat liver

DOI:  https://doi.org/10.3390/ijms26062670
Clin Exp Med. 2025 Mar 25. 25(1): 94

Calcium channels as pharmacological targets for cancer therapy.

Xiaozhen Liu, Changyun Feng, Li Yan, Jili Cao, Xinping Zhu, Mingqian Li, Guizhi Zhao.

  Ca2+, as critical second messengers in biological processes, plays a pivotal role in the regulation of diverse cellular signaling pathways. The dysregulation of calcium signaling is intricately linked to the progression of various cancers. The capacity of Ca2+ to modulate cell death and proliferation, along with its potential for pharmacological manipulation, presents a promising avenue for the development of novel cancer therapeutics. This review provides a comprehensive overview of the classification of Ca2+ channels and their mechanisms of action in oncogenesis, explores the application of Ca2+ blockers in cancer treatment, and underscores the importance of conducting further clinical trials.

Keywords:  Calcium channels; Cancer therapy; Pharmacological targets

DOI:  https://doi.org/10.1007/s10238-025-01632-z
Semin Cancer Biol. 2025 Mar 25. pii: S1044-579X(25)00053-7. [Epub ahead of print]

The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.

Haowen Jiang, Jiangbin Ye.

  Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.

Keywords:  Warburg effect; cell dedifferentiation; epigenetic remodeling; metabolic reprogramming; metabolic therapy; mitochondrial dynamics; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.006
Acta Pharmacol Sin. 2025 Mar 25.

The role of calcium signaling in organotropic metastasis of cancer.

Yong-Hao Li, Chu-Run Zheng, Yue Liu, Ke Wang, Fan-Fan Zhou, Xin Dong, Tao Yuan, Qiao-Jun He, Hong Zhu, Bo Yang.

  Tumor metastasis is an important event in cancer progression, representing an enduring and irrevocable hallmark of cancers. The causes of tumor metastasis are complex and diverse. Arising evidence shows that the dysregulation of calcium signaling plays a crucial role in its initiation and progress. Calcium is an essential secondary messenger that regulates signaling pathways associated with tumor metastasis. The transient accumulation of calcium potentially promotes the advancement of tumor metastasis, while calcium-dependent proteins and calcium-related channels also significantly contribute to such malignant process. Thus, compounds specially targeting calcium channels, transporters or pumps may be therapeutic approaches prohibiting tumor metastasis. This review focuses on exploring the roles of calcium ions, calcium-dependent proteins and calcium-related channels in organotropic metastasis of cancer and its clinical applications in the treatment of metastatic cancers.

Keywords:  calcium signaling; calcium-dependent proteins; calcium-related channels; cancer metastasis

DOI:  https://doi.org/10.1038/s41401-025-01537-3
Cell Calcium. 2025 Mar 18. pii: S0143-4160(25)00023-5. [Epub ahead of print]127 103014

Crosstalk between calcium and reactive oxygen species signaling in cancer revisited.

Trayambak Pathak, J Cory Benson, Priscilla W Tang, Mohamed Trebak, Nadine Hempel.

  The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.

Keywords:  Ca(2+); ROS; Redox signaling; cancer

DOI:  https://doi.org/10.1016/j.ceca.2025.103014
Sci Rep. 2025 Mar 25. 15(1): 10235

Relative expression orderings based prediction of treatment response to Anti-PD-1 immunotherapy in advanced melanoma.

Yaru Gao, Yue Huo, Lingli Wang, Jiayi Ruan, Lanzhen Chen, Hongdong Li, Guini Hong.

  Programmed cell death protein 1 (PD-1) plays a critical role in immune tolerance and evasion within the tumor microenvironment, and anti-PD-1 immunotherapy has shown efficacy in treating advanced melanoma. However, response rates vary significantly among patients, necessitating the identification of reliable biomarkers to predict treatment efficacy. Based on within-sample relative expression orderings, we analyzed RNA sequencing data from melanoma patients to construct a predictive model comprising gene pairs associated with treatment response. The model's performance was validated across multiple independent datasets and assessed for correlations with immune infiltration and survival outcomes. The constructed 15-pair model achieved a prediction accuracy of 100% in training datasets and 89.47% in validation sets. Validation in melanoma patients lacking treatment response data revealed significant differences between predicted responders and non-responders across datasets, with the model being an independent prognostic factor. Increased immune cell infiltration was observed in responders, correlating with higher expression levels of key immune checkpoint genes. The relative expression orderings-based model shows promise as a tool for predicting responses to anti-PD-1 therapy in melanoma patients, supporting personalized treatment strategies.

Keywords:  Biomarker; Melanoma; REOs; anti-PD-1 immunotherapy

DOI:  https://doi.org/10.1038/s41598-025-94931-0
Int J Mol Sci. 2025 Mar 19. pii: 2768. [Epub ahead of print]26(6):

A New Perspective on the Role of Alterations in Mitochondrial Proteins Involved in ATP Synthesis and Mobilization in Cardiomyopathies.

Melissa Vázquez-Carrada, María Magdalena Vilchis-Landeros, Héctor Vázquez-Meza, Daniel Uribe-Ramírez, Deyamira Matuz-Mares.

  The heart requires a continuous energy supply to sustain its unceasing contraction-relaxation cycle. Mitochondria, a double-membrane organelle, generate approximately 90% of cellular energy as adenosine triphosphate (ATP) through oxidative phosphorylation, utilizing the electrochemical gradient established by the respiratory chain. Mitochondrial function is compromised by damage to mitochondrial DNA, including point mutations, deletions, duplications, or inversions. Additionally, disruptions to proteins associated with mitochondrial membranes regulating metabolic homeostasis can impair the respiratory chain's efficiency. This results in diminished ATP production and increased generation of reactive oxygen species. This review provides an overview of mutations affecting mitochondrial transporters and proteins involved in mitochondrial energy synthesis, particularly those involved in ATP synthesis and mobilization, and it examines their role in the pathogenesis of specific cardiomyopathies.

Keywords:  ATP synthesis; cardiomyopathies; mitochondria; mitochondrial DNA; point mutations

DOI:  https://doi.org/10.3390/ijms26062768
Curr Oncol. 2025 Feb 21. pii: 121. [Epub ahead of print]32(3):

CD8+CD28+PD1- T Cells as a Prognostic Biomarker in Endometrial Cancer.

Yufei Nie, Lin Yang, Yanan Zhang, Hongyan Guo.

  Endometrial cancer (EC) is an immunogenic tumor, with CD8+ T cells playing a pivotal role in antitumor immunity. Overexpression of PD1 suppresses T cell function by inhibiting CD28, a critical co-stimulatory molecule. Classifying CD8+ T cells based on PD1 and CD28 expression provides valuable insights into the immune microenvironment of EC. Peripheral blood samples from 120 EC patients and tumor tissue samples from 81 EC patients were analyzed via flow cytometry. CD8+ T cells were categorized according to PD1 and CD28 expression, and their associations with clinical characteristics were systematically evaluated. Peripheral CD28-/CD8+ and PD1+/CD8+ T cell proportions were significantly associated with several high-risk factors, including deep myometrial invasion, and LVSI, as well as metabolic disorders such as dyslipidemia. Peripheral CD28+PD1-/CD8+ T cells were associated with stage, grade, and LVSI, inversely correlated with age, and elevated in patients with hypertension or dyslipidemia. Tumor-infiltrating CD28+PD1-/CD8+ T cells were associated with tumor grade and LVSI, with multivariate analysis identifying low proportions as an independent predictor of relapse. In summary, CD8+CD28- and CD8+PD1+ T cells are linked to high-risk clinical features in EC, while tumor-infiltrating CD8+CD28+PD1- T cells serve as a key independent prognostic marker for relapse. Additionally, CD8+CD28-, CD8+PD1+, and CD8+CD28+PD1- T cell proportions in PBMC are closely associated with metabolic disorders, emphasizing their potential as biomarkers for immune and metabolic interactions in EC.

Keywords:  CD28; PD1; endometrial cancer; immune microenvironment; prognosis

DOI:  https://doi.org/10.3390/curroncol32030121
J Immunother. 2025 Mar 24.

High Expression of Calreticulin Affected the Tumor Microenvironment and Correlated With Worse Prognosis in Patients With Triple-Negative Breast Cancer.

Xi Cao, Xinyu Ren, Yu Song, Qiang Sun, Feng Mao, Songjie Shen, Chang Chen, Yidong Zhou.

Calreticulin (CALR) preserves reticular homeostasis by maintaining correct protein folding within the endoplasmic reticulum. Immunogenic cell death (ICD) is a regulated form of cell death and could activate adaptive immune response. As one of the damage-associated molecular patterns during ICD process, surface-exposed CALR resulted in the activation of adaptive immune response. Here, we evaluated the expression patterns of CALR in a cohort of 231 untreated triple-negative breast cancer (TNBC) and determined correlations between CALR expression and clinicopathologic parameters, programmed cell death ligand 1 (PD-L1) expression in immune cells (ICs), and survival. In addition, we analyzed a TNBC data set from The Cancer Genome Atlas to explore the relationship between mRNA expression of CALR and clinicopathologic features, IC infiltration, and survival. Tissue microarray results showed that high CLAR was strongly correlated with advanced stage (P = 0.022), shorter disease-free survival (P = 0.008) and overall survival (P = 0.002), and independently predicted prognosis in TNBC. Spearman analyses demonstrated that CALR negatively correlated with PD-L1 in ICs (r = -0.198, P = 0.003). Patients with low CALR and high PD-L1 in ICs had the best disease-free survival (P = 0.013) and overall survival (P = 0.004) compared with other patients, especially the patients with high CALR and low PD-L1 in ICs. In the "The Cancer Genome Atlas" cohort, CALR mRNA expression in tumors was significantly higher than that in normal tissues (P < 0.001). CALR expression was strongly and positively related to other ICD-related genes. These findings demonstrated that the expression of CALR could independently predict the prognosis in patients with TNBC, and it may play a potential synergistic role in treatments involving immunotherapy.

DOI: https://doi.org/10.1097/CJI.0000000000000553
Anticancer Agents Med Chem. 2025 Mar 24.

Unraveling the Role of Tumor-infiltrating Immune Cells in Modulating Cancer Drug Resistance.

Shima Mehrabadi.

  Tumor-infiltrating immune cells (TIICs) have been identified as critical components in the development of cancer drug resistance. This review aims to discuss the various types of TIICs, such as macrophages and T cells, that have been linked to cancer drug resistance. Furthermore, we explore the mechanisms by which TIICs contribute to drug resistance and how these mechanisms may differ across various tumor types. Additionally, we examine the potential of immune checkpoint inhibitors in combination with traditional cancer therapies as a strategy to overcome TIIC-mediated cancer drug resistance. In conclusion, this review provides an in-depth analysis of the current knowledge on the role of TIICs in cancer drug resistance and highlights potential avenues for future research to develop more effective treatment strategies. The findings presented in this review emphasize the importance of understanding the complex interactions between cancer cells and the immune system in order to develop novel therapeutic approaches that can overcome TIIC-mediated cancer drug resistance.

Keywords:  Tumor-infiltrating immune cells; cancer drug resistance; immune cell modulation; macrophages.; tumor microenvironment

DOI:  https://doi.org/10.2174/0118715206365310250310081445
J Transl Med. 2025 Mar 24. 23(1): 366

Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.

Rui Wang, Jie Wang, Jing Yu, Zhiqiang Li, Minfang Zhang, Yuhu Chen, Fen Liu, Dongmei Jiang, Jingfei Guo, Xiaomei Li, Yun Wu.

   BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Recent studies indicate that Mitochondrial fusion protein 2 (Mfn2) maintains intracellular calcium (Ca2+) homeostasis via the mitochondria-associated endoplasmic reticulum membranes (MAMs) pathway, thereby inhibiting PASMCs proliferation and reducing pulmonary artery pressure. However, the precise mechanisms remain unclear.
METHODS: This study explored the roles of Mfn2 and IP3R3 in PAH progression by assessing their expression in lung tissues of a monocrotaline (MCT)-induced PAH rat model. Immunoprecipitation assays were performed to confirm the interaction between Mfn2 and IP3R3. PASMCs were treated with either silenced or overexpressed Mfn2 and exposed to TNF-ɑ to observe effects on ER stress, IP3R3 expression, mitochondrial Ca2+ transport, and mitochondrial integrity. We also evaluated the effects of 4-phenylbutyric acid (4-PBA) and cistanche phenylethanol glycosides (CPGs) on the Mfn2-IP3R3 interaction in a TNF-α-induced PAH cell model, focusing on Ca2+ transport and mitochondrial structure.
RESULTS: Mfn2 expression was significantly down-regulated in the MCT-induced PAH rat model. Inhibition of ER stress upregulated Mfn2 expression, downregulated IP3R3 expression, increased mitochondrial Ca2+ concentration, and reduced autophagy, improving pulmonary hemodynamics and vascular remodeling. Overexpression of Mfn2 reduced ER stress, decreased IP3R3 expression, decreased mitochondrial Ca2+ transport, and restored mitochondrial integrity. Immunoprecipitation assays confirmed the interaction between Mfn2 and IP3R3. Inhibition of IP3R3 elevated Mfn2 levels, yielding similar beneficial effects as Mfn2 overexpression. 4-PBA and CPGs modulated the Mfn2-IP3R3 signaling axis, effectively inhibiting PAH progression.
CONCLUSIONS: Mfn2 mediates mitochondrial Ca2+ transport via IP3R3, suppressing PASMCs proliferation and pulmonary vascular remodeling, underscoring Mfn2's potential in regulating metabolic processes and vascular remodeling in PAH. These findings provide new insights for developing PAH-targeted therapeutics and establish a theoretical basis for traditional Chinese medicine in PAH prevention and treatment.

Keywords:  Ca2+ homeostasis; Endoplasmic reticulum stress; Mfn2 interact with IP3R3; Mitochondrial autophagy; Pulmonary artery hypertension

DOI:  https://doi.org/10.1186/s12967-025-06384-8
Adv Sci (Weinh). 2025 Mar 26. e2416596

Targeted STING Activation Using Modified Ultrasound-Responsive Microbubbles Enhances Immune Checkpoint Blockade Against Melanoma.

Sina Khorsandi, Kristin Huntoon, Yifan Wang, Adam Woodward, Abin Antony, Connor Endsley, Nazia Hafeez, Jared L Edwards, Nicole McCuen, Prasanna G Alluri, Betty Y S Kim, Wen Jiang, Jacques Lux.

  Despite the recent successes of immune checkpoint inhibitors (ICIs) in treating advanced melanoma, durable clinical responses still remain limited. To boost immune responses, agents that target immune regulators, such as the Stimulator of Interferon Genes (STING) agonist cyclic GMP-AMP (cGAMP), are being investigated. However, their clinical translation is impeded by poor serum stability, rapid tissue clearance, and T-cell death due to off-target activation. Recently, a novel strategy termed Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) has been reported to selectively deliver cGAMP directly into the cytosol of antigen-presenting cells with spatiotemporal control. The resulting activation of STING and downstream proinflammatory pathways produces antitumor effects in murine models of breast cancer. Herein, this study reports that MUSIC provides curative results in aggressive murine models of melanoma as well. Under ultrasound exposure, MUSIC reduces tumor size, increases overall survival, and synergizes with ICIs to bridge innate and adaptive immunities. The results from this study represent MUSIC's ability to produce potent immune responses in melanoma, thus indicating its potential as an adjuvant for cancers where ICI is the current standard of care.

Keywords:  cancer therapy; drug delivery; immunotherapy; microbubbles; sting pathway; ultrasound

DOI:  https://doi.org/10.1002/advs.202416596
Bioengineering (Basel). 2025 Mar 09. pii: 268. [Epub ahead of print]12(3):

Targeting Ion Channels: Blockers Suppress Calcium Signals and Induce Cytotoxicity Across Medulloblastoma Cell Models.

Darani Ashley Thammavongsa, Taylor N Jackvony, Markus J Bookland, Min D Tang-Schomer.

  Medulloblastoma (MB) groups 3 and 4 lack targeted therapies despite their dismal prognoses. Ion channels and pumps have been implicated in promoting MB metastasis and growth; however, their roles remain poorly understood. In this study, we repurposed FDA-approved channel blockers and modulators to investigate their potential anti-tumor effects in MB cell lines (DAOY and D283) and primary cell cultures derived from a patient with MB. For the first time, we report spontaneous calcium signaling in MB cells. Spontaneous calcium signals were significantly reduced by mibefradil (calcium channel blocker), paxilline (calcium-activated potassium channel blocker), and thioridazine (potassium channel blocker). These drugs induced dose-dependent cytotoxicity in both the DAOY and D283 cell lines, as well as in primary cell cultures of a patient with group 3 or 4 MB. In contrast, digoxin and ouabain, inhibitors of the Na/K pump, reduced the calcium signaling by over 90% in DAOY cells and induced approximately 90% cell death in DAOY cells and 80% cell death in D283 cells. However, these effects were significantly diminished in the cells derived from a patient with MB, highlighting the variability in drug sensitivity among MB models. These findings demonstrate that calcium signaling is critical for MB cell survival and that the targeted inhibition of calcium pathways suppresses tumor cell growth across multiple MB models.

Keywords:  Na/K ATPase inhibitors; calcium modulators; calcium signaling; channel blockers; cytotoxicity; ion channels; potassium channels; spontaneous calcium waves; targeted therapies; tumor cytotoxicity

DOI:  https://doi.org/10.3390/bioengineering12030268
Discov Oncol. 2025 Mar 24. 16(1): 382

Identification of autophagy-related immune targets for enhancing immunotherapy in pancreatic cancer aggressiveness.

Qianxi Deng, Linju Wu, Jin He, Fan Wu, Zheng Jiang.

   BACKGROUND: Pancreatic cancer (PC) presents significant challenges in oncology, with metastasis critically affecting patient outcomes. Autophagy-related genes (ARGs)'s involvement in influencing immune activity and metastasis in PC remains inadequately understood.
AIM: This study seeks to identify and validate five ARGs that could serve as immune targets, enhancing enhancing Pancreatic cancer metastasis (PCM)'s prognostic models and informing immunotherapy strategies.
METHODS: ARGs that were diffentially expressed were screened, followed by Cox regression and LASSO analyses to pinpoint five genes linked to overall survival (OS). A prognostic model was developed and validated using ROC curves. Functional analyses, including GO and KEGG, were performed to elucidate ARG mechanisms. Immune infiltration and TFs/microRNA/mRNA networks were assessed to understand ARG-immune cell interactions. Experimental validation employed real-time PCR, IHC, and Western blotting, supported by TCGA data. Functional assays explored RHEB's role in PC, particularly its interaction with LC3.
RESULTS: Five ARGs (CASP1, RHEB, CHMP2B, MYC, and HDAC6) were identified, contributing to a robust prognostic model where low-risk individuals showed significantly longer OS. The model demonstrated high AUC scores, indicating strong prognostic capability. CD8 T cells and Treg cells' elevated levels were observed in metastatic subjects. RHEB knockdown suppressed cancer cell proliferation and invasion, with a negative correlation between RHEB and LC3, suggesting a role in autophagy-mediated modulation of PC metastasis.
CONCLUSION: This study introduces a novel prognostic model incorporating five ARGs, highlighting their potential as immune targets for cancer immunotherapy. The negative correlation between RHEB and LC3 suggests a therapeutic pathway for PCM intervention, laying the groundwork for more effective anti-cancer strategies. These findings advance the identification of novel immune targets and signaling pathways, aligning with precision medicine goals in cancer treatment.

Keywords:  Autophagy-related genes; Immune infiltration; Metastasis; Pancreatic cancer; Prognostic model; RHEB

DOI:  https://doi.org/10.1007/s12672-025-02190-2
RSC Adv. 2025 Mar 21. 15(12): 9027-9033

PD-L1 blockade peptide-functionalized NaGdF4 nanodots for efficient magnetic resonance imaging-guided immunotherapy for breast cancer.

Zhenzhen Hu, Yunkai Bao, Xiaodong Li, Zhuheng Li, Peihong Teng, Guifeng Liu, Zhenxin Wang.

Immune checkpoint blockade (ICB) inhibitors have shown great promise for the treatment of numerous types of cancers, including triple-negative breast cancer (TNBC), by interrupting immunosuppressive checkpoints. Herein, programmed cell death ligand 1 (PD-L1) blockade peptide-functionalized NaGdF4 nanodots (designated as PDL1-NaGdF4 NDs) were prepared for magnetic resonance imaging (MRI)-guided TNBC immunotherapy through covalent conjugation of the PD-L1 blockade peptide (sequence, CALNNCVRARTR) with tryptone-capped NaGdF4 NDs (designated as Try-NaGdF4 NDs). MDA-MB-231 tumor could be easily tracked using in vivo MRI with PDL1-NaGdF4 ND enhancement because the as-prepared PDL1-NaGdF4 NDs have a high longitudinal relaxivity (r 1) value (22.8 mM-1 S-1) and accumulate in the tumor site through binding with programmed cell death ligand-1 (PD-L1)-overexpressed cells. A series of in vitro/in vivo results demonstrated that the PDL1-NaGdF4 NDs could effectively suppress MDA-MB-231 tumor growth in mice (66% volume ratio) by inhibiting migration and proliferation of tumor cells. In addition, the results of pharmacokinetic study showed that the PDL1-NaGdF4 NDs were excreted from the body through the kidneys. These results highlight the potential of PDL1-NaGdF4 NDs as a biocompatible nanomedicine for TNBC diagnosis and immunotherapy.

DOI: https://doi.org/10.1039/d4ra08800j
Front Immunol. 2025 ;16 1545012

Therapeutic strategies for adrenocortical carcinoma: integrating genomic insights, molecular targeting, and immunotherapy.

Jing Sun, Jiaxuan Huai, Wenhui Zhang, Tianyu Zhao, Run Shi, Xuanbin Wang, Minglun Li, Xuehua Jiao, Xiqiao Zhou.

  Adrenocortical carcinoma (ACC) is an uncommon and highly aggressive cancer originating in the adrenal cortex, characterized by a high likelihood of recurrence and unfavorable survival rates, particularly in the advanced disease stages. This review discusses the complex molecular pathogenesis of ACC, focusing on critical pathways implicated in the tumorigenesis and providing potential targets for therapy: the Wnt/β-catenin signaling pathway, the IGF2/IGF1R axis, and the apoptosis pathway regulated by p53. Current treatment strategies include surgical resection and mitotane, the sole adrenolytic agent approved by the FDA; however, its effects in advanced disease are suboptimal. Cytotoxic chemotherapy combined with mitotane may be applied, but survival benefits are limited so far. In the following review, we outline emerging targeted therapies, such as mTOR inhibitors and tyrosine kinase inhibitors (TKIs), which show favorable preclinical and clinical data, especially in treatment-resistant ACC. We also emphasize the possible role of immune checkpoint inhibitors (ICIs) in the management of ACC, although their effectiveness is still under study. Upcoming trends in treatment involve forms of personalized medicine, where molecular profiling is integrated to identify actionable biomarkers for administered therapies. This review will attempt to provide a comprehensive framework on how recent breakthroughs in the genomics of ACC, coupled with advances in targeted therapies and immunotherapy, can improve management.

Keywords:  adrenocortical carcinoma; genomic insights; immunotherapy; molecular pathogenesis; targeted therapies

DOI:  https://doi.org/10.3389/fimmu.2025.1545012
Nat Commun. 2025 Mar 24. 16(1): 2854

A protease-cleavable liposome for co-delivery of anti-PD-L1 and doxorubicin for colon cancer therapy in mice.

Yixuan Liu, Ying Xie, Yuling Chen, Jialun Duan, Chunjie Bao, Jinling Wang, Hexuan Feng, Mengjie Wang, Yuxin Ren, Peishan Li, Qian Luo, Jiarui Xu, Min Jiang, Yanchen Men, Yang Wu, Jianwei Li, Guiling Wang, Wanliang Lu.

Immune checkpoint blockade therapy using programmed cell death 1 (PD1) or programmed death ligand 1 (PD-L1) has made significant progress in the treatment of advanced cancers, with some patients achieving long-term remission without clinical recurrence. However, only a minority of colon cancer patients respond to the therapy. Here, we report a protease-cleavable anti-PD-L1 antibody liposome, eLipo anti-PD-L1, for enhancing colon cancer therapy. In vivo, eLipo anti-PD-L1 is cleaved by legumain at colon cancer site into pegylated anti-PD-L1 and cancer-homing doxorubicin liposome. Functional assessments show cancer-targeting, legumain-responding, tumor-penetrating, and immune-activating effects, as well as efficacy in treating colon cancer-bearing mice in vivo. Further mechanistic analysis implicates genes related to T cell differentiation and T cell receptor signaling as potential molecular mediators. Lastly, human colorectal cancer tissue evaluations verify expressions of PD-L1 and legumain, hinting a potential translatability. Our study thus suggests that eLipo anti-PD-L1 may be a feasible vector for co-delivery of immunochemotherapy for colon cancer.

DOI: https://doi.org/10.1038/s41467-025-57965-6
Front Bioeng Biotechnol. 2025 ;13 1563701

Mitochondria targeted nanoparticles for the treatment of mitochondrial dysfunction-associated brain disorders.

Amy Claire Buck, Gerald J Maarman, Admire Dube, Soraya Bardien.

  Mitochondria play a significant role in several cellular activities and their function in health and disease has become an important area of research. Since the brain is a high-energy-demanding organ, it is particularly vulnerable to mitochondrial dysfunction. This has been implicated in several brain disorders including neurodegenerative, psychiatric and neurological disorders, e.g., Parkinson's disease and schizophrenia. Significant efforts are underway to develop mitochondria-targeting pharmaceutical interventions. However, the complex mitochondrial membrane network restricts the entry of therapeutic compounds into the mitochondrial matrix. Nanoparticles (NPs) present a novel solution to this limitation, while also increasing the stability of the therapeutic moieties and improving their bioavailability. This article provides a detailed overview of studies that have investigated the treatment of mitochondrial dysfunction in brain disorders using either targeted or non-targeted NPs as drug delivery systems. All the NPs showed improved mitochondrial functioning including a reduction in reactive oxygen species (ROS) production, an improvement in overall mitochondrial respiration and a reversal of toxin-induced mitochondrial damage. However, the mitochondrial-targeted NPs showed an advantage over the non-targeted NPs as they were able to improve or rescue mitochondrial dynamics and biogenesis, and they required a lower concentration of the in vivo therapeutic dosage of the drug load to show an effect. Consequently, mitochondria-targeted NPs are a promising therapeutic approach. Future studies should exploit advances in nanotechnology, neuroscience and chemistry to design NPs that can cross the blood-brain barrier and selectively target dysfunctional mitochondria, to improve treatment outcomes.

Keywords:  brain disorders; mitochondria-targeted nanoparticles; mitochondrial dysfunction; nanomedicine; therapy

DOI:  https://doi.org/10.3389/fbioe.2025.1563701
Sci Adv. 2025 Mar 28. 11(13): eadt3311

Mycobacterium tuberculosis phagosome Ca2+ leakage triggers multimembrane ATG8/LC3 lipidation to restrict damage in human macrophages.

Di Chen, Antony Fearns, Maximiliano G Gutierrez.

The role of canonical autophagy in controlling Mycobacterium tuberculosis (Mtb), referred to as xenophagy, is understood to involve targeting Mtb to autophagosomes, which subsequently fuse with lysosomes for degradation. Here, we found that Ca2+ leakage after Mtb phagosome damage in human macrophages is the signal that triggers autophagy-related protein 8/microtubule-associated proteins 1A/1B light chain 3 (ATG8/LC3) lipidation. Unexpectedly, ATG8/LC3 lipidation did not target Mtb to lysosomes, excluding the canonical xenophagy. Upon Mtb phagosome damage, the Ca2+ leakage-dependent ATG8/LC3 lipidation occurred on multiple membranes instead of single or double membranes excluding the noncanonical autophagy pathways. Mechanistically, Ca2+ leakage from the phagosome triggered the recruitment of the V-ATPase-ATG16L1 complex independently of FIP200, ATG13, and proton gradient disruption. Furthermore, the Ca2+ leakage-dependent ATG8/LC3 lipidation limited Mtb phagosome damage and restricted Mtb replication. Together, we uncovered Ca2+ leakage as the key signal that triggers ATG8/LC3 lipidation on multiple membranes to mitigate Mtb phagosome damage.

DOI: https://doi.org/10.1126/sciadv.adt3311
Adv Sci (Weinh). 2025 Mar 27. e2415530

High Sugar Induced RCC2 Lactylation Drives Breast Cancer Tumorigenicity Through Upregulating MAD2L1.

Bowen Zheng, Yunhao Pan, Fengyuan Qian, Diya Liu, Danrong Ye, Bolin Yu, Seng Zhong, Wenfang Zheng, Xuehui Wang, Baian Zhou, Yuying Wang, Lin Fang.

  Lactylation is a novel post-translational modification mediated by lactate, widely present in the lysine residues of both histone and non-histone proteins. However, the specific regulatory mechanisms and downstream target proteins remain unclear. Herein, it is demonstrated that the RCC2 protein may serve as a critical link between material metabolism and cell division, promoting the rapid proliferation of breast cancer under high glucose conditions. Mechanistically, the activation of glycolysis leads to an increase in lactate. Then, acyltransferase KAT2A mediates RCC2 lactylation at K124, which assists RCC2 in recruiting free SERBP1, thereby stabilizing MAD2L1 mRNA. The lactylation of RCC2 mediates the activation of the cellular MAD2L1 signaling pathway and contributes to the progression of breast cancer. A small molecule inhibitor slows down cell proliferation by binding to the RCC2 active pocket and specifically blocking RCC2 lactylation. The findings elucidate the mechanism behind the upregulation of MAD2L1 in murine tumors associated with a high-sugar diet as reported in prior study and suggest a novel therapeutic strategy of targeting RCC2 lactylation to restrict the rapid proliferation of breast cancer cell in a high-lactate microenvironment.

Keywords:  MAD2L1; RCC2; SERBP1; cell division; high sugar diet

DOI:  https://doi.org/10.1002/advs.202415530