bims-meract 2025-11-02 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–11–02
eighteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
Metformin induces ferroptosis associated with lipidomic remodeling in AML.
Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy.
Fuelling resistance: Lipid metabolic rewiring in cancer response to chemotherapy and radiotherapy.
Targeting GPX2 to disrupt lipid homeostasis and enhance cisplatin sensitivity in diffuse gastric cancer.
MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.
Proline Intake Dampens Radiosensitivity in Prostate Cancer Cells by Targeting PRODH/MAPK Pathway.
MOGAT2 suppresses colorectal cancer progression through ACSM1-mediated lipid metabolic reprogramming.
Targeting serine metabolism vulnerability in omipalisib-resistant acute myeloid leukemia with phosphoglycerate dehydrogenase inhibitors.
ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer.
Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.
PSMA-targeted CAR-macrophages drive glycolytic reprogramming for enhanced prostate cancer immunotherapy.
Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.
Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.
Targeting neutral sphingomyelinase 2 by cambinol decreases cell proliferation and migration of metastatic castration-resistant prostate cancer cells.
A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.
Smart dendrimer nanogels boost mRNA-based cancer therapy via synergistic glycolysis inhibition and immune activation.
Cytoplasmic HMGB1 promotes and interacts with BECN1 through ZNF460 to induce autophagy and accelerate radioresistance in colorectal cancer cells.

Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

  The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.

Keywords:  TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate

DOI:  https://doi.org/10.1016/j.molcel.2025.10.002
Blood Adv. 2025 Oct 31. pii: bloodadvances.2025016155. [Epub ahead of print]

Metformin induces ferroptosis associated with lipidomic remodeling in AML.

Dominique Sternadt, Diego A Pereira-Martins, Prodromos Chatzikyriakou, Luise Albuquerque-Simões, Ming Yang, Douglas R Silveira, Albertus Tj Wierenga, Isabel Weinhäuser, Shanna M Hogeling, Lieve Oudejans, Pilar Casares-Alaez, Jean-Emmanuel Sarry, Christian Frezza, Gerwin A Huls, Lynn Quek, Jan Jacob Schuringa.

Metabolic reprogramming is a hallmark of cancer, essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes and inhibiting this pathway has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable due to significant side effects. Thus, repurposing safe FDA-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles predicting treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in ROS levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, co-treatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, while iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.

DOI: https://doi.org/10.1182/bloodadvances.2025016155
Radiol Oncol. 2025 Oct 27.

Heterogenous mitochondrial ultrastructure and metabolism of human glioblastoma cells: differences between stem-like and differentiated cancer cells in response to chemotherapy.

Urban Bogataj, Metka Novak, Simona Katrin Galun, Klementina Fon Tacer, Milos Vittori, Cornelis J F Van Noorden, Barbara Breznik.

   BACKGROUND: Glioblastoma stem-like cells (GSCs) contribute to the resistance of glioblastoma (GBM) tumors to standard therapies. The background of the resistance of GSCs to the chemotherapeutic agent temozolomide is not yet fully understood in the context of cellular metabolism and the role of mitochondria. The aim of this study was to perform a detailed ultrastructural characterization of the mitochondria of GSCs prior and post temozolomide exposure and to compare it to differentiated GBM cells.
MATERIALS AND METHODS: Patient-derived and established GBM cell lines were used for the study. The ultrastructure of the mitochondria of the examined cell lines was assessed by transmission electron microscopy. The microscopic analysis was complemented and compared by an analysis of cell metabolism using Seahorse extracellular flux analysis.
RESULTS: We found that the metabolic profile of GSCs is quiescent and aerobic. Their elongated mitochondria with highly organized cristae are indicating increased biogenesis and mitochondrial fusion and corresponds to a more oxidative phosphorylation (OXPHOS)-dependent metabolism. The metabolism of GSCs is dependent on OXPHOS and there are no changes in defective mitochondria fraction after the treatment with temozolomide. In contrast, differentiated GBM cells with fragmented mitochondria, which have less organized cristae, are more energetic and glycolytic. Temozolomide treatment induced ultrastructural mitochondrial damage in differentiated GBM cells.
CONCLUSIONS: We demonstrated differences in mitochondrial ultrastructure and cellular metabolism between GSCs and differentiated GBM cells in response to temozolomide, suggesting that mitochondria play an important role in the resistance of GSCs to temozolomide. This study provides a basis for further studies addressing GSC chemotherapy resistance in the context of mitochondrial structure and function.

Keywords:  chemotherapy resistance; glioblastoma; metabolism; mitochondria ultrastructure; stem cells

DOI:  https://doi.org/10.2478/raon-2025-0056
Biomed Pharmacother. 2025 Oct 30. pii: S0753-3322(25)00909-6. [Epub ahead of print]193 118715

Fuelling resistance: Lipid metabolic rewiring in cancer response to chemotherapy and radiotherapy.

Viktoria Piatrikova, Eva Kocianova, Lucia Skvarkova, Tereza Golias.

  Resistance to chemotherapy and radiotherapy remains a major challenge in cancer treatment and is closely linked to treatment failure and poor patient outcome. While metabolic rewiring is a well-established hallmark of cancer, the specific role of lipid metabolism in promoting therapy resistance has only recently gained attention. Cancer cells modulate lipid metabolic pathways to support survival, maintain redox balance, enable membrane remodelling, enhance DNA repair, and evade cell death under therapeutic stress. They do so by altering fatty acid synthesis, fatty acid oxidation, and lipid storage, ultimately contributing to resistance to genotoxic therapies. These adaptations also intersect with non-apoptotic cell death pathways such as ferroptosis and cuproptosis, and are regulated in part by post-translational modifications including acetylation and lipidation. Moreover, chemotherapy and radiotherapy can further promote metabolic adaptations that increase lipid dependence and reinforce resistant phenotypes. Recognizing these metabolic dependencies has revealed potential molecular targets within lipid metabolism, offering new opportunities to overcome resistance by co-targeting metabolic plasticity alongside standard therapies. Therapeutic strategies that disrupt lipid-driven adaptations may therefore help re-sensitise resistant tumours, enhance therapeutic efficacy, and expand treatment options.

Keywords:  Cuproptosis; Fatty acids; Ferroptosis; Lipid droplets; Lipid metabolism; Lipidation; Therapy resistance

DOI:  https://doi.org/10.1016/j.biopha.2025.118715
Cell Death Discov. 2025 Oct 27. 11(1): 491

Targeting GPX2 to disrupt lipid homeostasis and enhance cisplatin sensitivity in diffuse gastric cancer.

Yanmei Zhu, Yichun Ma, Wenying Li, Yani Pan, Yue Wang, Qiange Ye, Yinya Pan, Ying Xiang, Ping Jiang, Yi Fang, Lei Xu, Na Liu, Gaifang Liu, Zhangding Wang, Guifang Xu.

Diffuse gastric cancer (DGC) is characterized by high malignancy and metastasis rate, and poorly understood etiology, culminating in dismal patient outcomes. Here, through comprehensive analysis, we identified that glutathione peroxidase 2 (GPX2) plays a pivotal role in the progression of DGC by regulating lipid metabolism. This study demonstrates that GPX2 is markedly upregulated in DGC tissues, establishing its potential as an independent prognostic indicator. Functionally, GPX2 suppression disrupts lipid droplet formation and lipid homeostasis, leading to increased acylcarnitine levels that impair mitochondrial function. This disruption synergizes with endoplasmic reticulum stress to trigger apoptosis in gastric cancer cells. Notably, inhibiting GPX2 enhances the efficacy of cisplatin by sensitizing cancer cells to apoptosis. These insights identify GPX2 not only as a vital prognostic biomarker but also as a promising therapeutic target for overcoming cisplatin resistance in DGC, offering new avenues for treatment strategies.

DOI: https://doi.org/10.1038/s41420-025-02771-8
Cell Mol Life Sci. 2025 Oct 28. 82(1): 371

MPC-mediated lactate production drives histone lactylation in dendritic cells to affect tumor progression and immunotherapy.

Bin Zhang, Anran Xu, Haowei Wang, Wei Yan, Qing Zhang, Shuang Wang.

  Lactate is an abundant oncometabolite in the tumor microenvironment (TME). Lactate driven by metabolic reprogramming leads to acidic microenvironment formation to promote the immune evasion of tumor cells and reduce the effectiveness of immunotherapy for patients with tumors. The expression of mitochondrial pyruvate carrier (MPC) is crucial for pyruvate metabolism, and its dysregulation can lead to the formation of an acidic microenvironment caused by excessive lactic acid. However, the impact of MPC on tumor metabolic processes and biological behavior, as well as how lactate impacts immunosuppression, remains unclear. Here, we found that MPC1 and MPC2, two subunits of MPC, were downregulated in patients with colorectal cancer (CRC). Co-overexpression of MPC1 and MPC2 decreased lactate levels and inhibited cell proliferation, migration and invasion in vitro and tumor growth in vivo in the setting of CRC. Knockdown of MPC1 or MPC2 increased lactate levels and promoted the proliferation, migration and invasion of CRC cells. Mechanistically, the accumulation of lactate promotes the elevation of histone lactylation levels, and MPC regulates the expression of CD33, a marker of dendritic cell (DC) maturation, via histone lactylation, decreasing CD8+ T cell functions. In addition, the overexpression of MPC increased the therapeutic effect of the anti-PD-1 antibody. Our findings reveal that MPC downregulation-mediated lactate production impacts DC maturation via histone lactylation-dependent transcriptional regulation to impair CD8+ T cell responses, suggesting that targeting MPC could enhance immunotherapy efficacy by modulating the TME.

Keywords:  CD33; Colorectal cancer; Dendritic cell; Histone lactylation; Mitochondrial pyruvate transporter carrier

DOI:  https://doi.org/10.1007/s00018-025-05881-9
Radiat Res. 2025 Oct 31.

Proline Intake Dampens Radiosensitivity in Prostate Cancer Cells by Targeting PRODH/MAPK Pathway.

Lei Chang, Xinzhou Deng, Shan Jiang, Cangyu Wang, Jingjing Chai, Le Zhou, Chao Tian, Yuanhui Tang, Zhiguo Luo, Lihua Duan, Yutao Yan.

Radiotherapy remains a standard treatment for prostate cancer (PCa), inducing tumor cell death and apoptosis. However, its efficacy depends on various factors, including tumor cell metabolism. In this study, we investigated whether alterations in proline metabolism influence the response of prostate cancer cells to radiation. The radiosensitivity of LNCaP and C4-2 cells after X-ray irradiation was assessed using colony formation and tumor-sphere assays, while Matrigel invasion assays evaluated in vitro cell invasion. We then examined the effect of radiation on proline dehydrogenase (PRODH) expression and MAPK/p-MAPK signaling via Western blotting. To further explore the role of proline metabolism in radiation response, we tested the impact of exogenous proline supplementation and PRODH knockdown on radiation efficacy in LNCaP and C4-2 cells using the same assays. Finally, in vivo validation was performed using xenograft tumor models in nude mice to determine how proline and PRODH modulation influences radiation outcomes. Our results demonstrated that X-ray irradiation significantly inhibited prostate cancer cell growth and invasion. However, this effect was attenuated by exogenous proline supplementation. Following irradiation, proline dehydrogenase (PRODH) expression was upregulated, while phosphorylated MAPK (p-MAPK) levels were downregulated. Notably, the suppressive effect of proline on radiation efficacy was abolished upon PRODH knockdown, suggesting a key role for proline metabolism in radiation response. In vivo studies further supported these findings: X-ray irradiation effectively suppressed tumor growth in xenograft mouse models, but this therapeutic effect was diminished when mice were treated with proline solution. These observations align with our in vitro data, reinforcing the modulatory role of proline metabolism in radiosensitivity. While radiotherapy demonstrates robust antitumor effects in prostate cancer, our findings reveal that proline metabolism significantly impairs radiation efficacy in both cellular and animal models.

DOI: https://doi.org/10.1667/RADE-25-00171.1
Funct Integr Genomics. 2025 Oct 27. 25(1): 226

MOGAT2 suppresses colorectal cancer progression through ACSM1-mediated lipid metabolic reprogramming.

Shaofeng Jiang, Ying He, Jiarui Jiang, Xinhan Zhao.

   OBJECTIVE: Colorectal carcinogenesis and progression are closely associated with metabolic dysregulation. The role of MOGAT2 in colorectal cancer (CRC) advancement and its underlying metabolic mechanisms remain unclear. This study aimed to explore how MOGAT2 influences tumorigenesis by modulating lipid metabolism.
METHODS: MOGAT2 expression was assessed in four CRC cell lines using qRT-PCR and Western blot. Functional consequences of MOGAT2 modulation were examined following siRNA-mediated knockdown or lentivirus-mediated overexpression in HCT116/SW620 cells. Assays measured cell proliferation, colony formation, apoptosis, invasion, and epithelial-mesenchymal transition (EMT). Key lipid metabolites and metabolic enzymes were analyzed. A CRC xenograft mouse model was used for in vivo validation. RNA sequencing and rescue experiments identified ACSM1 as a key downstream mediator.
RESULTS: MOGAT2 knockdown enhanced cell proliferation, colony formation, and invasion, as well as inhibited apoptosis. While its overexpression significantly suppressed malignant phenotypes, induced apoptosis, and inhibited EMT. Mechanistically, MOGAT2 modulated lipid metabolism by reducing FFA accumulation and regulating cholesterol transport, accompanied by downregulation of lipid synthesis enzymes (GPAT2, GPAT3, and GAAT). In vivo, MOGAT2 overexpression inhibited tumor growth, improved histopathology, and restored lipid balance. Crucially, ACSM1 was identified as a critical downstream effector. Silencing ACSM1 abolished the tumor-suppressive effects of MOGAT2 overexpression, reinstating aggressive growth, suppression of apoptosis, EMT, and metabolic dysregulation.
CONCLUSION: MOGAT2 functions as a tumor suppressor in CRC by inhibiting proliferation, promoting apoptosis, and suppressing invasion/EMT via ACSM1-mediated metabolic reprogramming, highlighting its potential as a therapeutic target.

Keywords:  ACSM1; Colorectal cancer; Lipid metabolic reprogramming; MOGAT2; Tumorigenesis

DOI:  https://doi.org/10.1007/s10142-025-01739-2
Biomed Pharmacother. 2025 Oct 27. pii: S0753-3322(25)00883-2. [Epub ahead of print]192 118689

Targeting serine metabolism vulnerability in omipalisib-resistant acute myeloid leukemia with phosphoglycerate dehydrogenase inhibitors.

Chi-Yang Tseng, Yu-Hsuan Fu, Da-Liang Ou, Hsin-An Hou, Hsiung-Fei Chien, Liang-In Lin.

  Acute myeloid leukemia (AML) is the most common acute leukemia that primarily affects older adults. Dysregulated PI3K/AKT/mTOR signaling pathway is a common abnormality in AML. Our previous study demonstrated the excellent cytotoxicity of dual PI3K/mTOR inhibitor omipalisib against AML cells. However, its clinical application remains challenging because of potential resistance mechanisms following kinase inhibitor administration. In this study, OCI-AML3-OR, an OCI-AML3 subline that is resistant to omipalisib, was established. Transcriptomics analysis revealed that the significant differentially expressed genes (DEGs) between parental and omipalisib-resistant AML cells were dominantly associated with cell cycle-related and nucleotide metabolism pathways. Metabolomic analysis in conjunction with metabolite enrichment analysis revealed a shift in glucose metabolism toward the pentose phosphate pathway (PPP) and serine synthesis pathway (SSP) in OCI-AML3-OR cells. OCI-AML3-OR cells exhibited enhanced proliferation by increasing purine synthesis dominated by SSP and PPP. Targeting phosphoglycerate dehydrogenase (PHGDH), a SSP rate-limiting enzyme, with NCT-503 and WQ-2101 resulted in increased reactive oxygen species levels and the induction of apoptosis in OCI-AML3-OR cells and another omipalisib-insensitive SKNO-1 cell in vitro. Furthermore, we found that, like OCI-AML cells, the exportin 1 (XPO1) inhibitors selinexor and eltanexor significantly induced cell cycle arrest and reduced PHGDH expression in OCI-AML3-OR cells. Finally, in vivo experiments demonstrated that both NCT-503 and selinexor significantly inhibited tumor growth and prolonged mouse survival without causing weight loss of OCI-AML3-OR xenografts. Therefore, treatment with PHGDH inhibitors could be a therapeutic strategy for refractory AML to PI3K/mTOR inhibitors. Relevant clinical trials are warranted.

Keywords:  Acute myeloid leukemia; Drug resistance; Omipalisib; Phosphoglycerate dehydrogenase inhibitor

DOI:  https://doi.org/10.1016/j.biopha.2025.118689
Proc Natl Acad Sci U S A. 2025 Nov 04. 122(44): e2502778122

ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer.

He Cui, Xueting Cai, Qiang Qian, Shuyuan Fan, Tian Li, Ting Wang, Haixuan Dai, Yunwei Song, Xiaoyan Sun, Peng Cao.

  Receptor tyrosine kinase pathway rewiring represents a fundamental mechanism underlying acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC). While posttranslational modifications facilitate aberrant activation of bypass signaling networks, the specific contribution of ZDHHC palmitoyl acyltransferase-mediated palmitoylation remains poorly characterized. Here, ZDHHC11-mediated palmitoylation contributes to osimertinib resistance in EGFR-mutant NSCLC. Patient samples, along with in vitro and in vivo functional studies, indicated that ZDHHC11 upregulation reduces the sensitivity of tumor cells to osimertinib by promoting malignant phenotype. Mechanistically, we establish AXL receptor tyrosine kinase as the critical substrate. ZDHHC11 catalyzes AXL palmitoylation at Cys869, inducing plasma membrane retention and constitutive activation. This triggers downstream PI3K-AKT signaling, with AXL knockout alleviating the effect of ZDHHC11-driven resistance. Crucially, pharmacological inhibition ZDHHC11-mediated palmitoylation with the broad-spectrum palmitoylation inhibitor 2-bromopalmitate effectively augmented the antitumor effects of osimertinib. Collectively, ZDHHC11 regulates osimertinib resistance in a palmitoylation-dependent manner. Targeting the ZDHHC11-AXL axis may provide a promising therapeutic strategy for the treatment of osimertinib-resistant EGFR-mutant NSCLC patients with high ZDHHC11 expression.

Keywords:  AXL; Osimertinib; Palmitoylation; ZDHHC11; non-small-cell lung cancer

DOI:  https://doi.org/10.1073/pnas.2502778122
Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00435-8. [Epub ahead of print]

Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer.

Zhengwei Wu, Zhenxun Wang, Seow Qi Ng, Jessica Alice Lidster, Paul Schwerd-Kleine, Zi Jin Cheryl Phua, Kai Lay Esther Peh, Yin Ying Ho, Ju Yuan, S Shathishwaran, Xun Hui Yeo, Ying Zhang, Yui Hei Jasper Chiu, Li Yieng Eunice Lau, Tony Kiat Hon Lim, Angela Takano, Eng Huat Tan, Anders Jacobsen Skanderup, Vinay Tergaonkar, Weiping Han, Ying Swan Ho, Daniel Shao Weng Tan, Wai Leong Tam.

  Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo. These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies.

Keywords:  CD147; MCT1; glucose stress; ketogenic diet; ketone metabolism; lung cancer; metabolic reprogramming; monocarboxylate transporter; tumor-initiating cells

DOI:  https://doi.org/10.1016/j.cmet.2025.10.001
J Hematol Oncol. 2025 Oct 29. 18(1): 95

PSMA-targeted CAR-macrophages drive glycolytic reprogramming for enhanced prostate cancer immunotherapy.

Yangli Xu, Duoli Xie, Chunhao Cao, Zhuqian Wang, Yue Ju, Lili Guan, Xuelong Li, Shanshan Wu, Luo Zhang, Chao Liang, Xiushan Yin.

  Although chimeric antigen receptor (CAR)-T cells have demonstrated remarkable efficacy against hematologic malignancies, their effectiveness in solid tumors is limited by poor tumor infiltration and severe cytokine release syndrome (CRS). CAR-macrophage (CAR-M) therapy has emerged as a promising alternative, leveraging the innate tumor-homing capacity of macrophages while enabling antigen-specific phagocytosis and immune activation without triggering CRS. Prostate-specific membrane antigen (PSMA) represents an ideal therapeutic target due to its high expression in prostate cancer cells. In this study, we engineered PSMA-specific CAR-M with potent anti-tumor activity against prostate cancer cells both in vitro and in vivo. PSMA-specific CAR-M exhibited strong antigen-dependent phagocytic capability and underwent polarization toward a pro-inflammatory, tumoricidal phenotype upon PSMA recognition. Mechanistically, interaction with PSMA-expressing prostate cancer cells induced metabolic reprogramming, characterized by enhanced glycolytic activity and suppressed oxidative phosphorylation, which reinforced the anti-tumor function of CAR-M. Our findings highlight PSMA-targeted CAR-M therapy as a promising immunotherapeutic approach for prostate cancer.

Keywords:  CAR-M; Immunotherapy; Metabolic reprogramming.; PSMA; Prostate cancer

DOI:  https://doi.org/10.1186/s13045-025-01743-w
Mol Biomed. 2025 Oct 27. 6(1): 87

Dihydroorotate dehydrogenase inhibition activates STING pathway and pyroptosis to enhance NK cell-dependent tumor immunotherapy.

Yongrui Hai, Ruizhuo Lin, Weike Liao, Shuo Fu, Renming Fan, Guiquan Ding, Junyan Zhuang, Bingjie Zhang, Yi Liu, Junke Song, Gaofei Wei.

  Cancer cells rely heavily on de novo pyrimidine synthesis. Inhibiting pyrimidine metabolism directly suppresses tumor growth and fosters immune activation within the tumor microenvironment. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis pathway. Inhibiting DHODH can reverse immune suppression and trigger a mild innate immune response. However, the impact of DHODH inhibition on natural killer (NK) cells remains to be explored. In this study, we found that DHODH inhibition promoted NK cell infiltration into tumors efficiently. Mechanistically, DHODH suppression induced mitochondrial oxidative stress, leading to mitochondrial DNA (mtDNA) release into the cytoplasm through voltage-dependent anion channel (VDAC) oligomerization and caspase-3 activation. This subsequently activated the stimulator of interferon gene (STING) pathway, triggered ferroptosis, and induced gasdermin E (GSDME) mediated pyroptosis in cancer cells. These changes collectively facilitated NK cell recruitment. Furthermore, infiltrated NK cells enhanced GSDME-dependent pyroptosis in tumor cells through granzyme release, establishing a positive feedback loop that amplified anti-tumor immunity. Additionally, we developed EA6, a novel DHODH inhibitor that is more effective at promoting NK cell infiltration. In summary, this study reveals that targeting pyrimidine metabolism activates a novel mechanism involving pyroptosis-ferroptosis crosstalk and STING pathway activation to enhance NK cell-mediated immunity. These finding opens new avenues for enhancing the efficacy of targeted nucleotide metabolism in cancer therapy.

Keywords:  CGAS-STING pathway; DHODH; NK cells; Pyrimidine metabolism; Pyroptosis

DOI:  https://doi.org/10.1186/s43556-025-00339-7
Cell Commun Signal. 2025 Oct 30. 23(1): 468

Ammonia metabolism and ammonia-induced cell death: role in cancer therapy.

Yan Xu, Jiafeng Wang, Aixiang Wu, Mengchuan Wang.

  Ammonia has long been regarded as the end-toxic product of hepatic metabolism. Under normal physiological conditions, ammonia is metabolized through the urea cycle; however, its metabolic imbalance is closely related to various diseases, including hepatic encephalopathy, liver fibrosis, and cancer. Ammonia-induced cell death, specifically the selective death of immune cells, has emerged in recent years as a new form of cell death in the field of tumor biology, offering a new perspective on the regulation of tumor cell fate. This review creatively focuses on the role of ammonia in tumorigenesis, development, and treatment resistance. We systematically reviewed the sources and dynamic balance of ammonia in the tumor microenvironment and found that it plays a key role in tumor metabolic reprogramming by regulating glutamine metabolism, mitochondrial function, and lysosomal stability in tumor cells. Ammonia can also induce the selective death of immune cells, reshape the immune cell map in the tumor microenvironment, and regulate the anti-tumor immune response. Mechanistically, we analyzed the multi-level network of ammonia metabolism regulation, including the role of glutamine synthetase, the mTOR signaling pathway, and epigenetic modification in ammonia death. In addition, this review emphasizes the importance of ammonia as a potential target for cancer therapy and proposes multimodal strategies combining metabolic regulation and immunotherapy to achieve precision in cancer treatment. Finally, the comprehensive map of ammonia in the tumor ecosystem was constructed, highlighting its potential clinical value as a new anti-cancer target.

Keywords:  Ammonia; Apoptosis; Autophagy; Immunotherapy; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-025-02504-5
J Pharmacol Exp Ther. 2025 Oct 09. pii: S0022-3565(25)40252-3. [Epub ahead of print]392(11): 103739

Targeting neutral sphingomyelinase 2 by cambinol decreases cell proliferation and migration of metastatic castration-resistant prostate cancer cells.

Dalal Dawud, Malvina Kartamyshev, Tanya Kumar, Uzair M Bilal, Lin Kang, Zakaria Y Abd Elmageed.

  Metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge in the treatment of advanced-stage prostate cancer, particularly among American men. Despite current therapeutic options, disease progression and resistance continue to limit patient outcomes. Therefore, the exploration of novel therapeutic strategies is urgently needed. This study investigates the anticancer potential of cambinol, a selective inhibitor of neutral sphingomyelinase 2, alone and in combination with apalutamide, in mCRPC cells. mCRPC cells were treated with different concentrations of cambinol and apalutamide. Cell viability assay was performed to determine the half-maximal inhibitory concentration for each drug. The effects of cambinol on colony formation and cell migration were assessed. Protein expression levels of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin signaling components were evaluated using immunoblotting analysis. Cambinol treatment at 0.1× and 0.5× half-maximal inhibitory concentration significantly reduced cell viability and colony formation in a dose-dependent manner, underscoring its antiproliferative potential. Combined treatment with cambinol and apalutamide led to a marked decrease in cell migration, suggesting synergistic effects in limiting metastatic behavior. Western blot analysis revealed the downregulation of neutral sphingomyelinase 2, nuclear factor κ B, extracellular signal-regulated kinase 1/2, and protein kinase B/mammalian target of the rapamycin, indicating suppression of key survival and proliferation pathways. This study provides new insights into the multifaceted anticancer effects of cambinol in mCRPC cells, including inhibition of cell viability, colony formation, and migration. The observed molecular changes support its role in modulating critical signaling pathways. These findings warrant further investigation into the therapeutic potential of cambinol, both as a monotherapy and in combination with standard therapies, for the treatment of mCRPC. SIGNIFICANCE STATEMENT: This study aimed to evaluate the antitumor effect of cambinol, a selective inhibitor of neutral sphingomyelinase 2, and its combination with apalutamide as a potential therapeutic strategy for metastatic castration-resistant prostate cancer.

Keywords:  Apalutamide; Cambinol; Castration-resistant prostate cancer; Cell proliferation; Migration; n-SMase2 inhibition

DOI:  https://doi.org/10.1016/j.jpet.2025.103739
Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01267-7. [Epub ahead of print]44(11): 116496

A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.

Ting Liu, Ji-Hao Zhou, Yongbo Gong, Ying Zhang, Yongcan Ma, Xiaowen Zhang, Mohammad Minhajuddin, Wenjie Song, Zixuan Zhuang, Ana Vujovic, Youli Lu, Ang Jia, Rongqun Guo, Ruobing Ren, Lu Zhou, Yu Xiong, Linzhang Huang, Xingrong Du, Tong-Jin Zhao, Peng Li, Craig T Jordan, Haobin Ye.

  Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine (AD), an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, AD binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Interestingly, intercellular heterogeneity in mitochondrial translation drives heterogeneous MMP states within the population, which is associated with stemness and chemoresistance. Intriguingly, this intra-population MMP difference stems not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis-a mechanism leukemia cells selectively activate to evade chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.

Keywords:  CP: cancer; alexidine; asparagine; leukemia stem cells; mitochondrial membrane potential; mitochondrial translation

DOI:  https://doi.org/10.1016/j.celrep.2025.116496
Bioact Mater. 2026 Feb;56 3-14

Smart dendrimer nanogels boost mRNA-based cancer therapy via synergistic glycolysis inhibition and immune activation.

Xianghao Xiao, Yue Gao, Aiyu Li, Yiyang Jia, Jingjing Li, Mengjiao Zhang, Ruiqi Ji, Mingwu Shen, Andrij Pich, Xiangyang Shi.

  Cancer mRNA vaccine has emerged as a promising immunotherapy approach. However, development of functional vehicles for safe and efficient mRNA delivery into immune cells (e.g., dendritic cells, DCs) remains to be challenging, and most of the mRNA-based vaccines just act on immune cells for improved anticancer immunity without additional input to tackle cancer cells, ultimately limiting the anticancer efficacy. Herein, we report the development of pH-responsive dual-action dendrimer nanogels (DNGs) to deliver gp100 mRNA as a potential nanovaccine. Mannose-conjugated generation 3 poly(amidoamine) dendrimers were crosslinked through dual functional polyethylene glycol with both ends of aldehyde groups to form pH-responsive DNGs. The DNGs with a size of 45.7 nm show excellent colloidal stability and cytocompatibility and allow dual-actions for DC-targeted mRNA delivery and cancer cell glycolysis inhibition. In a subcutaneous mouse melanoma model, the DNG/mRNA vaccine exerted glycolytic inhibition effect and triggered robust antitumor immune responses to suppress the tumor growth, especially in combination with anti-PD-L1 antibody-mediated immune checkpoint blockade. Meanwhile, the local vaccination of the vaccine enabled effective tumor occurrence prevention. Such a DNG-based mRNA vaccine with dual actions on both DCs and cancer cells may be applied for improved immunotherapy of other cancer types.

Keywords:  Cancer immunotherapy; Dendrimers; Glycolysis inhibition; Mannose; Nanogels; mRNA vaccine

DOI:  https://doi.org/10.1016/j.bioactmat.2025.10.008
Front Immunol. 2025 ;16 1642915

Cytoplasmic HMGB1 promotes and interacts with BECN1 through ZNF460 to induce autophagy and accelerate radioresistance in colorectal cancer cells.

Yuhui Han, Xiuxin Liu, Wenjiong Sheng, Ruixue Kuang, Yan Zhang, Xinyu Jia, A M Abd El-Aty, Tao Hu, Bin Wang, Yanchao Ma.

  Radioresistance results in relapse and treatment failure in locally advanced colorectal cancer (CRC) patients. HMGB1 is reportedly associated with radioresistance in esophageal squamous cell carcinoma and breast cancer. However, its role in the response of CRC to radiotherapy has not been fully elucidated. Thus, we explored the role and underlying mechanism of HMGB1 in CRC radioresistance. The total amount of HMGB1 and its translocation from the nucleus to the cytoplasm increased after irradiation. Functional studies revealed that HMGB1 enhanced the proliferation and autophagy of CRC cells after irradiation. Mechanistically, HMGB1 can regulate the transcription factor ZNF460, which combines with the BECN1 promoter to promote the release of BECN1 into the cytoplasm after irradiation. Moreover, HMGB1 directly interacts with BECN1 in the cytoplasm, thereby resulting in CRC radioresistance. Finally, the protein expression levels of BECN1, which was positively correlated with HMGB1, were significantly increased in human CRC tissues and associated with TNM stage and poor prognosis in patients with CRC. Our findings revealed that HMGB1 plays a vital role in CRC radioresistance by regulating autophagy through binding with BECN1. Given the efficacy of HMGB1 modulation in CRC suppression and radioresistance, HMGB1 has emerged as a potential therapeutic molecule for CRC treatment.

Keywords:  BECN1; HMGB1; ZNF460; autophagy; colorectal cancer; radioresistance

DOI:  https://doi.org/10.3389/fimmu.2025.1642915