bims-meract 2026-03-08 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–03–08
twenty-two papers selected by
Andrea Morandi, Università degli Studi di Firenze

Adenylate kinase 4 promotes radioresistance by suppressing radiation-induced ferroptosis through metabolic regulation in glioblastoma.
PKM2 Lactylation Promotes Colorectal Cancer Vasculogenic Mimicry and Bevacizumab Resistance by Facilitating FOSL1 Super-Enhancer Formation.
L-lactate-driven PSMD14 lactylation and stabilization promote lactate production and ferroptosis resistance via ENO1 in intrahepatic cholangiocarcinoma.
Cancer-associated fibroblasts drive gemcitabine resistance in pancreatic cancer by promoting ferroptosis resistance via the PAX6/PAK3/SLC3A2 axis.
Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.
1,25D3 reprograms mitochondrial quality control via sirtuin and sensitizes glioblastoma to chemotherapy.
Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.
ANO6 Confers Paclitaxel Resistance by Targeting Ferroptosis in Cervical Cancer.
Metronomic Chemotherapy Induces Metabolic Reprogramming in Cancer Cells that Modulates Mature Regulatory Dendritic Cell Function to Stimulate Antitumor Immunity.
FASN inactivation-induced progranulin (GRN) expression promotes lysosome-dependent cell death to suppress leukemogenesis.
Inhibition of Autophagy Reveals ATR Protein Kinase as a Key Mediator of Cisplatin Sensitivity in Osteosarcoma.
tRF-1432 orchestrates RBMS1-IMPDH2 regulatory control to drive purine-dependent chemoresistance in breast cancer.
ACT001 synergizes with temozolomide-based chemoradiotherapy to cure refractory glioblastoma by targeting TNF-CXCL10-CD8+ T-cell immunity.
SIRT3 promotes oxaliplatin sensitivity in hepatocellular carcinoma by promoting ferroptosis through endoplasmic reticulum stress response.
The lncRNA DAMER selectively guides m6A-dependent regulation of ATF4 and asparagine metabolism under nutrient stress in cancer.
DNA-PKcs Promotes Therapy Resistance and Metastatic Recurrence in Neuroblastoma.
Targeting ACSS2 disrupts metabolic-epigenetic crosstalk to restore apoptosis and temozolomide chemosensitivity in pancreatic neuroendocrine tumors.
DysUFMylation reprograms immunosuppressive neutrophils to potentiate anti-PD-1 therapy in hepatocellular carcinoma.
Targeting the lipid metabolism proteins FASN and GPAM in alveolar type II cells decreases lung metastasis.
Tumor-restraining fibroblasts emerge after chemotherapy specifically in responders.
Native chromatome profiling reveals hundreds of metabolic enzymes in the nucleus across tissues.
Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.

Apoptosis. 2026 Mar 05. pii: 87. [Epub ahead of print]31(3):

Adenylate kinase 4 promotes radioresistance by suppressing radiation-induced ferroptosis through metabolic regulation in glioblastoma.

Byeongsoo Kim, Hyunkoo Kang, Junhyeong Park, Sujin Park, HyeSook Youn, BuHyun Youn.

  Primary solid tumors often exhibit accelerated glucose metabolism yet generate limited ATP due to reduced flux through the tricarboxylic acid (TCA) cycle. However, how these distinct metabolic alterations contribute to therapeutic resistance-and whether they represent targetable metabolic vulnerabilities-remains unclear. Here, we identify adenylate kinase 4 (AK4), a mitochondrial regulator of adenylate homeostasis, as a key mediator of radioresistance in glioblastoma (GBM) cells. We found that AK4 is upregulated in radioresistant GBM cells, where it suppresses mitochondrial oxidative phosphorylation to maintain redox homeostasis and promote cell survival following ionizing radiation (IR). Moreover, AK4 maintains elevated intracellular AMP, leading to the activation of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism. AMPK activation subsequently inhibits acetyl-CoA carboxylase (ACC), suppressing cellular lipid synthesis. Through these mechanisms, AK4 limits IR-induced ferroptosis and contributes to radioresistance. Notably, we demonstrate that entinostat, a class I histone deacetylase (HDAC) inhibitor, downregulates AK4 expression and enhances the sensitivity of GBM cells to IR both in vitro and in vivo. In conclusion, our study reveals that AK4 promotes radioresistance in GBM by coordinating mitochondrial redox regulation and AMPK-mediated lipid metabolism, highlighting AK4 as a promising therapeutic target for overcoming GBM radioresistance.

Keywords:  AK4; Ferroptosis; Glioblastoma; Radioresistance

DOI:  https://doi.org/10.1007/s10495-026-02314-1
Cancer Res. 2026 Mar 05.

PKM2 Lactylation Promotes Colorectal Cancer Vasculogenic Mimicry and Bevacizumab Resistance by Facilitating FOSL1 Super-Enhancer Formation.

Weihao Li, Jianhong Peng, Jiahua He, Leen Liao, Da Kang, Weili Zhang, Weifeng Wang, Ruowei Wang, Song Wang, Yuanbin Liao, Long Yu, Qingjian Ou, Yujing Fang, Xiaojun Wu, Peirong Ding, Zhizhong Pan, Chi Zhou, Junzhong Lin.

Despite the clinical utility of bevacizumab in advanced colorectal cancer (CRC), resistance remains a major challenge. Here, we unveiled a lactate-mediated mechanism driving vasculogenic mimicry (VM) and bevacizumab resistance through PKM2 lactylation. PKM2 lactylation at K206 by AARS1 promoted PKM2 nuclear translocation and interaction with FOSL1. PKM2 binding facilitated FOSL1-dependent super-enhancer formation and target gene transcription, which contributed to CRC cell VM. Genetic or pharmacological inhibition of PKM2 lactylation disrupted VM and synergized with bevacizumab in patient-derived pre-clinical models, significantly improving therapeutic efficacy. Together, this study reveals lactylation as a metabolic switch linking cancer glycolytic reprogramming to transcriptional rewiring and proposes targeting PKM2 lactylation to enhance the anti-tumor activity of bevacizumab in CRC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3520
Cancer Lett. 2026 Mar 03. pii: S0304-3835(26)00157-6. [Epub ahead of print] 218394

L-lactate-driven PSMD14 lactylation and stabilization promote lactate production and ferroptosis resistance via ENO1 in intrahepatic cholangiocarcinoma.

Dong Cai, Guo-Chao Zhong, Zhibo Zhao, Menglin Chen, Qing Tao, Xin Dai, Degong Jia, Lve Cheng, Zhenru Wu, Shengwei Li, Jianping Gong, Junhua Gong.

  Targeting ferroptosis is a promising treatment strategy for intrahepatic cholangiocarcinoma (ICC) given the limited number of currently available therapeutic drugs. However, the heterogeneity of tumor cells and their resistance to ferroptosis pose difficulties in the implementation of this strategy. Here, we constructed a novel ferroptosis resistance score (FRS) to quantitatively assess the ferroptosis resistance status of ICC samples. Next, we found that glycolysis is closely associated with the FRS and verified that L-lactate drives ferroptosis resistance via PSMD14 in vitro and in vivo. Mechanistically, L-lactate promoted the K100 lactylation of PSMD14 to delay proteasome-mediated degradation. PSMD14 subsequently interacted with ENO1 to decrease ENO1 K63-linked ubiquitination and inhibited lysosome-mediated ENO1 degradation. Importantly, targeting PSMD14 inhibited L-lactate production and ferroptosis resistance through ENO1 and significantly increased the efficacy of anti-PD-1 treatment. Furthermore, PSMD14 and ENO1 were highly expressed in tumor tissues and closely associated with a poor ICC prognosis. Overall, our study reveals the importance of the L-lactate/PSMD14/ENO1 axis in regulating ferroptosis resistance in ICC, suggesting a novel therapeutic target and strategy for treating this disease.

Keywords:  ENO1; ICC; L-lactate; PD-1; PSMD14; ferroptosis

DOI:  https://doi.org/10.1016/j.canlet.2026.218394
Cancer Lett. 2026 Mar 03. pii: S0304-3835(26)00144-8. [Epub ahead of print] 218381

Cancer-associated fibroblasts drive gemcitabine resistance in pancreatic cancer by promoting ferroptosis resistance via the PAX6/PAK3/SLC3A2 axis.

Huimou Chen, Jing Hu, Zhengyu Wu, Cao Dai, Honghui Jiang, Zhihua Li, Zhiqiang Fu, Di Cheng, Shangyou Zheng.

  Gemcitabine serves as a cornerstone chemotherapeutic agent for pancreatic cancer; however, gemcitabine resistance remains a major obstacle to improving treatment efficacy. The aim of our study was to elucidate the underlying mechanisms of gemcitabine resistance in pancreatic cancer. Through transcriptomic sequencing of gemcitabine-resistant pancreatic cancer cells, we found that p21-activated kinase 3 (PAK3) was significantly upregulated in both gemcitabine-resistant cell lines and tissues. In gemcitabine-resistant pancreatic cancer cells, PAK3 phosphorylates serine 175 of SLC3A2, thereby enhancing the stability of SLC3A2, promoting ferroptosis resistance in pancreatic cancer cells, and mediating gemcitabine resistance. Further mechanistic studies elucidated that FGF1 secreted by cancer-associated fibroblasts upregulates PAX6, which promotes the transcription of PAK3. Subsequently, PAK3 phosphorylates SLC3A2 at Serine 175, preventing its recognition and ubiquitination by the E3 ligase STUB1. This process enhances SLC3A2 protein stability by thwarting its degradation, culminating in acquired gemcitabine resistance. This study unveils a novel mechanism of gemcitabine resistance in pancreatic cancer and provides a potential therapeutic target for reversing drug resistance.

Keywords:  Cancer-associated fibroblasts; Chemoresistance; Ferroptosis; Gemcitabine; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.canlet.2026.218381
Cancer Res. 2026 Mar 02. 86(5): 1095-1097

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Mohammadreza Alizadeh-Ghodsi, Andrew S Goldstein.

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4807
Mol Ther. 2026 Mar 05. pii: S1525-0016(26)00191-7. [Epub ahead of print]

1,25D3 reprograms mitochondrial quality control via sirtuin and sensitizes glioblastoma to chemotherapy.

Karrie M Kiang, Yixiong Shen, Yogesh K H Wong, Bo Chen, Junbo Liao, Anza Mnahal, Wanjun Tang, Zhiyuan Zhu, Shuhan Cao, Carmen S C Lo, Sang Jin Lee, Hongbo Guo, Liyang Zhang, Gilberto Ka-Kit Leung.

Tumor cells adapt to therapeutic stress by preserving mitochondrial integrity through mitophagy, but excessive mitophagy can overwhelm this adaptative mechanism and precipitate mitochondrial collapse. Here, we demonstrate that 1,25-dihydroxyvitamin D3 (1,25D3) reduces glioblastoma resistance to the standard chemotherapeutics temozolomide by driving mitophagic overload and mitochondrial dysfunction. We identified mitochondrial sirtuin SIRT4 as a key downstream effector of mitochondrial metabolism and quality control triggered by 1,25D3-induced mitochondrial stress. Pharmacological levels of 1,25D3 activate mitophagy by transcriptionally upregulating SIRT4 through vitamin D receptor (VDR) signaling. SIRT4, which is frequently downregulated in glioblastoma, suppresses glioblastoma glutamine metabolism by inhibiting glutamate dehydrogenase activity and limiting α-ketoglutarate availability, thereby integrating metabolic stress with enhanced mitophagy. This VDR-SIRT4 axis shifts mitophagy from a cytoprotective process to a lethal pathway, selectively sensitizing tumor cells while sparing normal astrocytes and brain tissue. By exploiting mitochondrial quality control as a metabolic vulnerability, 1,25D3 enhances chemotherapeutic efficacy and provides a translational rationale for repurposing 1,25D3 in resistant glioblastoma.

DOI: https://doi.org/10.1016/j.ymthe.2026.03.006
Nat Commun. 2026 Mar 06. pii: 2244. [Epub ahead of print]17(1):

Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.

Hongli Zhang, Zixuan Wang, Yiqi Zhao, Xiya Deng, Jian Zhang, Fei Shang, Hongjie Zhang, Yan Liu, Hongbo Wang, Yating Yang, Huiyu Lin, Bo Zhang, Ce Liu, Fan Guo, Ruolin Zhang, Qipeng Yuan, Yue Feng, Shi-Zhong Luo, Wei-Dong Chen, Yan-Dong Wang.

Cancer cells reprogramme translation and metabolism to fuel tumorigenesis. Here, we show that hepatocellular carcinoma (HCC) paradoxically maintains low tyrosine levels despite increased uptake and reduced metabolism, redirecting tyrosine to translation via MYC-driven upregulation of tyrosyl-tRNA synthetase 1 (YARS1) and tRNA-TyrGUA. Restricting tyrosine translation availability (RTTA) via dietary limitation, YARS1/tRNA-TyrGUA ablation, tyrosine degradation (TAL), or YARS1 inhibition (tyrosinol) disturbs this adaptation, leading to the mitigation of tumorigenesis and extension of survival. Mechanistically, RTTA reduces tyrosine codon-dependent translation of mitochondrial complex I subunit NDUFB8 and lipid regulator SCD1, causing complex I misassembly, oxidative phosphorylation failure, and lipid peroxidation-induced ferroptosis. Genome-wide CRISPR screening identifies that loss of GPX4 and BCL2 by genetic manipulation or pharmacological treatment enhances the ability of RTTA to inhibit hepatocellular carcinogenesis. Our findings establish RTTA as a therapeutic strategy targeting tyrosine dependency and highlight combinatorial targeting of translation-metabolism crosstalk and ferroptosis pathways in liver cancer.

DOI: https://doi.org/10.1038/s41467-026-70112-z
Biofactors. 2026 Mar-Apr;52(2):52(2): e70070

ANO6 Confers Paclitaxel Resistance by Targeting Ferroptosis in Cervical Cancer.

Yanming Cao, Yuping Peng, Jian Shen.

  Paclitaxel (PTX) resistance limits cervical cancer therapy. Ferroptosis suppression via GPX4 and redox remodeling has emerged as a resistance mechanism, but upstream regulators remain unclear. To determine whether ANO6 drives PTX resistance by inhibiting ferroptosis and to define the ANO6-GPX4 axis mechanistically and therapeutically. Transcriptomic analyses, immunohistochemistry on clinical specimens, and cervical cancer cell models with gain/loss of ANO6 were combined with ferroptosis assays, mitochondrial imaging, apoptosis/viability assays, and Co-IP/CHX chase to assess ANO6-GPX4 interaction and stability. GPX4 transcriptional control was probed by ChIP-qPCR and dual-luciferase. PTX sensitivity was tested in vitro and in xenografts, with or without the ferroptosis inducer RSL3. ANO6 was overexpressed in cervical cancer and associated with worse prognosis. ANO6 knockdown reduced GPX4, SLC7A11, and NRF2, increased ACSL4, elevated lipid peroxidation and iron load, disrupted mitochondrial integrity, and heightened PTX cytotoxicity; ANO6 overexpression had opposite effects. ANO6 physically associated with GPX4 and preserved its protein stability; NRF2 enhanced GPX4 promoter activity, supporting a dual (post-translational/transcriptional) maintenance of GPX4 under ANO6 control. In PTX-resistant cells, ANO6 was upregulated; its depletion restored ferroptosis and PTX sensitivity, whereas GPX4 overexpression rescued resistance. In vivo, ANO6 overexpression promoted tumor growth and PTX resistance, while PTX + RSL3 synergistically suppressed tumors and reversed GPX4-axis signaling. ANO6 confers PTX resistance by sustaining GPX4-dependent ferroptosis evasion and mitochondrial homeostasis. Targeting the ANO-GPX4 axis, alone or combined with ferroptosis induction, may improve chemotherapy sensitivity in cervical cancer.

Keywords:  ANO6; cervical cancer; chemoresistance; ferroptosis; paclitaxel

DOI:  https://doi.org/10.1002/biof.70070
Cancer Res. 2026 Mar 05.

Metronomic Chemotherapy Induces Metabolic Reprogramming in Cancer Cells that Modulates Mature Regulatory Dendritic Cell Function to Stimulate Antitumor Immunity.

Zhenji Deng, Chuqing Zhang, Hanmiao Wei, Zhihao Hu, Guanxiang Hua, Zhe Li, Jiawei Wu, Tingxiang He, Yunlong Wang, Yinglin Cai, Liufen Long, Yuhao Li, Guibo Li, Yupei Chen, Chen Wei, Jun Ma, Xiaoyu Liang.

The efficacy of chemotherapy depends partly on the ability to induce anti-tumor immunity. A better understanding of how different chemotherapy modes mediate antitumor immune responses could provide insights for developing optimized treatment modalities. Here, we demonstrated that metronomic chemotherapy, a mode of frequent and regular administration of chemotherapeutic drugs at lower doses, induced robust CD8+ T cell-dependent anti-tumor immune memory by modulating activity of mature regulatory dendritic cells (mregDCs). Mechanistically, by imposing more frequent stress on tumor cells, metronomic chemotherapy induced sustained activation of ATF4, leading to metabolic reprogramming of tumor cells and enhanced asparagine (Asn) release into the tumor microenvironment. Functioning as a ligand, Asn directly bound to AXL on mregDCs, inhibiting AXL kinase activity and downregulating PD-L1 expression. Consequently, mregDCs with reduced PD-L1 expression fostered the generation of more memory-like CD8+ T cells during their interactions. Overall, this study unveils critical biological events driving antitumor immune memory formation under therapeutic stress and provides a rationale for optimizing chemotherapy modalities.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3669
Cell Rep. 2026 Mar 03. pii: S2211-1247(26)00120-8. [Epub ahead of print]45(3): 117042

FASN inactivation-induced progranulin (GRN) expression promotes lysosome-dependent cell death to suppress leukemogenesis.

Meng Su, Qinglin Li, Zhiyi Lv, Xinshu Xie, Yating Lu, Yaohui He, Hanqi Liu, Hui Cao, Jie Ouyang, Qiao Zhang, Xuezhen Ma, Yexin Yang, Ailing Zou, Kang Liu, Shuqian Xu, Ji Li, Lili Chen, Xin Lu, Jie Yang, Caiming Wu, Lu Liu, Lei Zhang, Yue Sheng, Yong Huang, Yang Mei.

  Cancer cells rely on lipogenesis in addition to exogenous lipid uptake, and fatty acid synthase (FASN) is aberrantly overexpressed in myeloid leukemia, yet its role in leukemogenesis is unclear. We show that FASN is essential for leukemogenesis. Its genetic ablation impairs leukemic cell growth, survival, and clonogenicity in vitro, and reduces disease burden in vivo, without significantly affecting normal hematopoiesis. We further identify a platensimycin derivative compound MS-C19 as a potent FASN inhibitor. MS-C19 suppresses growth and clonogenicity in clinical acute myeloid leukemia (AML) samples. Mechanistically, FASN inhibition or deficiency activates lysosomal and inflammatory gene programs, inducing lysosomal membrane permeabilization and associated cell death but not lysosome biogenesis. We further identify that GRN, a lysosomal and neuroinflammatory gene, is potently transcribed by TFEB upon FASN inhibition. GRN depletion reverses the anti-leukemic effects of FASN loss. Our findings establish FASN as a therapeutic target and support its pharmacological inhibition by MS-C19 for leukemia treatment.

Keywords:  CP: cancer; fatty acid synthase; lysosome-dependent cell death; myeloid leukemia; platensimycin derivatives; progranulin

DOI:  https://doi.org/10.1016/j.celrep.2026.117042
Cancer Med. 2026 Mar;15(3): e71658

Inhibition of Autophagy Reveals ATR Protein Kinase as a Key Mediator of Cisplatin Sensitivity in Osteosarcoma.

Janice S Pereira, Gabriel Rosa, Aine Pears, Beata Burczynska, Britta Stordal, Scott J Roberts, Helen C Roberts.

   INTRODUCTION: Osteosarcoma (OS) is the most common primary malignant bone tumor. Although the introduction of chemotherapy has improved the survival rate of OS patients, chemoresistance remains a major clinical problem underlying poor survival outcome. This study investigated the role of autophagy in OS chemoresistance and identified ATR as a novel upstream regulator linking DNA damage signaling, autophagy, and chemoresistance.
RESULTS: Elevated levels of autophagy were found in advanced grade and stage OS tumors, and higher autophagy levels were shown to be associated with poorer OS disease outcome. Chemotherapy significantly increased autophagy levels in HOS-143B cells, while autophagy inhibition by autophagy-related gene 7 knockout (ATG7-/-) significantly enhanced cisplatin (CIS) sensitivity in HOS-143B cells. A kinase screen revealed a reduction in the phosphorylation of p53 (S15) in ATG7-/- HOS-143B cells. ATR phosphorylates p53 at S15 responsible for DNA Damage Response (DDR), and ATR inhibition increased CIS sensitivity of HOS-143B cells via apoptosis. Subsequent analysis verified that ATR inhibition decreased phosphorylation of p53 at S15 and blocked autophagy in CIS-treated HOS-143B cells.
CONCLUSION: These findings highlight ATR inhibition as a unique therapeutic strategy that simultaneously disrupts DDR signaling and autophagy, thereby enhancing CIS sensitivity. Targeting ATR could reduce the required CIS dosage, limit treatment-associated toxicity, and ultimately improve survival and clinical outcomes for OS patients.

Keywords:  ATG7; ATR; autophagy; chemoresistance; osteosarcoma

DOI:  https://doi.org/10.1002/cam4.71658
Cancer Lett. 2026 Mar 04. pii: S0304-3835(26)00171-0. [Epub ahead of print] 218408

tRF-1432 orchestrates RBMS1-IMPDH2 regulatory control to drive purine-dependent chemoresistance in breast cancer.

Yuhan Dai, Xiaowei Wu, Xin Cheng, Jingqi Shang, Ziyi Yu, Yiqin Xia, Shengbin Pei, Yakun Kang, Jiangdong Jin, Shui Wang, Hui Xie, Yangyang Cui.

  Chemoresistance remains a major obstacle to effective breast cancer therapy and is driven in part by metabolic reprogramming and dysregulated RNA-mediated signaling. Although tRNA-derived fragments (tRFs) have emerged as important regulators of cellular stress responses, their roles in drug resistance remain incompletely understood. Here, using high-throughput sequencing, we identified tRF-1432 as a markedly upregulated tRF in chemoresistant breast cancer tissues and cell lines, which was further validated in clinical specimens. Functional assays and syngeneic tumor models demonstrated that tRF-1432 enhances resistance to adriamycin by promoting tumor cell survival and suppressing apoptosis under chemotherapeutic stress. Mechanistically, tRF-1432 is a 5'-tRNAˆVal-CAC-derived fragment generated by angiogenin cleavage and directly interacts with the RNA-binding protein RBMS1. This interaction attenuates RBMS1-mediated destabilization of IMPDH2 mRNA, leading to increased IMPDH2 expression. As a result, purine metabolic reprogramming is enhanced, intracellular GTP levels are elevated, and proliferative and survival signaling is sustained in the presence of chemotherapy. Importantly, pharmacological inhibition of IMPDH2 using mycophenolic acid (MPA), an FDA-approved drug, effectively reversed chemoresistance both in vitro and in vivo. Collectively, our findings establish a previously unrecognized tRF-1432/RBMS1/IMPDH2 regulatory axis that drives metabolic adaptation and chemoresistance in breast cancer, highlighting this pathway as a potential therapeutic target for overcoming drug resistance.

Keywords:  Breast cancer; Chemoresistance; IMPDH2; RBMS1; tRF-1432

DOI:  https://doi.org/10.1016/j.canlet.2026.218408
Front Pharmacol. 2026 ;17 1745656

ACT001 synergizes with temozolomide-based chemoradiotherapy to cure refractory glioblastoma by targeting TNF-CXCL10-CD8+ T-cell immunity.

Ya Shu, Ze-Hua Ding, Pan-Pan Gao, Qi An, Li-Qin Wu, Xin-Ran Zhang, Hai-Feng Jiang, Cheng Miao, Mei-Ting Peng, Xiao-Qian Chen, Jun Cai, Feng Liu.

  Glioblastoma multiforme (GBM), a highly invasive brain tumor, is severely restricted in T-cell infiltration and anti-tumor activity due to its immunosuppressive microenvironment. However, commonly used preclinical GBM mouse models cannot fully recapitulate the refractoriness of human GBM or effectively distinguish therapeutic efficacy. In this study, we evaluated the efficacy and mechanisms of therapies based on the novel sesquiterpene lactone small-molecule compound, ACT001, using the refractory G422TN-GBM mouse model. ACT001 alone exerted evident anti-G422TN-GBM effects in vivo and in vitro, but it only slightly prolonged animal survival. ACT001 combined with concurrent radiotherapy and temozolomide (RT/TMZ) exerted synergistic effects by suppressing tumor progression and extending animal survival. Importantly, the RT/TMZ/ACT001 regimen could achieve cure (long-term survival, >100 d, 26.7%) and immune cure (passing the tumor-rechallenge assay, >100 d, 12.5%) in G422TN mice. However, combining the anti-PD-1 antibody (αPD-1) with RT/TMZ/ACT001 did not further improve survival. Mechanistically, RT/TMZ/ACT001 substantially activated the tumor necrosis factor (TNF) pathway, inducing tumor cells and stromal cells in the microenvironment to express the chemokine C-X-C motif chemokine 10 (CXCL10), thereby promoting T-cell infiltration, especially CD8+ T cell, into the tumor site. Pharmacological inhibition of the TNF signaling pathway with R-7050 completely abolished the synergistic efficacy of RT/TMZ/ACT001. Taken together, our results demonstrate that ACT001 combined with RT/TMZ can overcome the immunosuppressive barrier of GBM to achieve immune cure in GBM via TNF-CXCL10-CD8+ signaling, strongly suggesting the priority of combining ACT001 with RT/TMZ rather than with αPD-1 in clinical trials.

Keywords:  ACT001; C-X- motif chemokine 10; CD8; TNF; chemoradiotherapy; glioblastoma

DOI:  https://doi.org/10.3389/fphar.2026.1745656
Pathol Res Pract. 2026 Feb 09. pii: S0344-0338(26)00051-8. [Epub ahead of print]281 156400

SIRT3 promotes oxaliplatin sensitivity in hepatocellular carcinoma by promoting ferroptosis through endoplasmic reticulum stress response.

Yinkai Xu, Chuntao Ma, Xiaolan Xu, Junhao Tu, Xin Chen, Xiaohua Yang, Ding Sun, Song Liu, Yi Wan, Lei Qin, Wen Gu, Haixin Qian.

  Hepatocellular carcinoma (HCC) is a common malignant tumor worldwide. The specific role of Sirtuin3 (SIRT3), a member of the Sirtuin family, in HCC, particularly regarding drug sensitivity, has not been fully elucidated. This study aimed to elucidate the mechanism by which SIRT3 modulates drug sensitivity in HCC. Expression prediction of target genes, survival analysis, and candidate protein screening were conducted using bioinformatics databases. After transfection of different plasmids in HCC cells, the expression of target genes was detected using RT-qPCR and Western blot. CCK-8 assay was used to assess the effect of SIRT3 overexpression on the proliferation ability of HCC cells. Additionally, changes in ferroptosis levels in HCC cells were reflected by detecting ferroptosis-related indicators (including ROS, MDA, GSH, and Fe2+ levels). SIRT3 was downregulated in HCC and its overexpression promoted sensitivity of HCC cells to oxaliplatin. Mechanistically, SIRT3 induced deacetylation modification and ubiquitination modification of GRP78, leading to a decrease in its stability and subsequent degradation of GRP78 protein. This process limited the correction of misfolded proteins during endoplasmic reticulum stress (ERS). The inhibition of the downstream transcription factor of ER stress ATF4 activation leads to the suppression of the anti-ferroptosis gene NRF2 transcription, thereby promoting ferroptosis in HCC cells and enhancing their sensitivity to oxaliplatin. In summary, SIRT3 enhances the sensitivity of HCC cells to oxaliplatin by promoting ferroptosis through the inhibition of GRP78-mediated ERS and regulation of the ATF4/NRF2 axis.

Keywords:  ER stress; Ferroptosis; HCC; Oxaliplatin sensitivity; SIRT3

DOI:  https://doi.org/10.1016/j.prp.2026.156400
Nat Cell Biol. 2026 Mar 06.

The lncRNA DAMER selectively guides m6A-dependent regulation of ATF4 and asparagine metabolism under nutrient stress in cancer.

Tianyu Tao, Xianming Feng, Yi Yang, Bangdong Liu, Jiaer Liang, Zishuo Chen, Shuqi Wang, Jiaqi Zhao, Xiuxiu Yang, Liyun Huo, Youhong Zhang, Zhen Gan, Weibin Wu, Jiayu Zeng, Yi Huang, Yaokai Ye, Xuemei Xu, Jianchen Yu, Ruohui Hong, Hongyu Guan, Jueheng Wu, Laixin Xia, Weiling He, Bo Li, Junchao Cai, Mengfeng Li.

How cancer cells couple metabolic stress sensing to orchestrate specific survival programmes is a key question. Here we show a long non-coding RNA (lncRNA)-guided epitranscriptomic mechanism orchestrating metabolic adaptation by controlling the stability of master stress regulator ATF4. Glucose or glutamine deprivation induces endoplasmic reticulum stress via reactive oxygen species-NRF2-dependent transcription of the lncRNA DAMER. Following its demethylation and nuclear retention by the m6A-eraser ALKBH5, DAMER acts as a scaffold, guiding ALKBH5 to demethylate and stabilize ATF4 mRNA through specific base-pairing. This provides an alternative post-transcriptional pathway for ATF4 upregulation, rewiring asparagine metabolism to promote cancer cell survival under stress. Furthermore, we identified the US FDA-approved drug elbasvir as a potent inhibitor of the DAMER-ALKBH5 interaction. Elbasvir dismantles this adaptive programme, targeting tumour asparagine dependency and exhibiting potent antitumour effects in preclinical models. Our findings reveal a paradigm for lncRNA-guided RNA demethylation that solves a target specificity enigma and offers a strategy targeting metabolic adaptation in cancer.

DOI: https://doi.org/10.1038/s41556-026-01905-z
Cancer Lett. 2026 Feb 27. pii: S0304-3835(26)00146-1. [Epub ahead of print] 218383

DNA-PKcs Promotes Therapy Resistance and Metastatic Recurrence in Neuroblastoma.

Mahnaz Norouzi, Subin Kim, Beibei Zhu, Chi Wang, Natalie Wu, Katherine Somers, Eddy Shih-Hsin Yang, B Mark Evers, Eric J Rellinger, Piotr Rychahou.

   PURPOSE: High-risk neuroblastoma presents a serious clinical challenge with survival rates below 50%. Disease relapse most commonly occurs at distant metastatic sites and remains the primary driver of poor outcomes, emphasizing the need for therapies to target drivers of relapse.
EXPERIMENTAL DESIGN: This study identified DNA-PKcs as a critical determinant of poor survival and metastatic relapse in neuroblastoma patients. We evaluated which therapeutic modality-chemotherapy or radiotherapy-when combined with DNA-PKcs inhibition, more effectively reduces metastatic burden and prevents recurrence.
RESULTS: Colony-forming assays revealed that established neuroblastoma colonies resist doxorubicin alone and require high-dose doxorubicin paired with DNA-PKcs inhibition to suppress progression. In contrast, low-dose radiotherapy in combination with DNA-PKcs inhibition effectively controlled colony progression. Maximal synergy between radiotherapy and DNA-PKcs inhibition was achieved when the inhibitor was administered within four hours post-irradiation. Chronic co-exposure to doxorubicin and peposertib encouraged emergence of therapy-resistant cells, whereas chronic co-exposure to radiotherapy combined with peposertib disrupted neuroblastoma cells self-renewal and prevented long-term colony maintenance. In neuroblastoma metastases, adding DNA-PKcs inhibition to doxorubicin improved efficacy but induced gastrointestinal side effects and failed to eradicate tumors; pairing it with low-dose, fractionated radiotherapy resulted in total lesion regression, impaired tumor self-renewal, and prevented systemic adverse effects.
CONCLUSIONS: Our findings correlate elevated DNA-PKcs levels with poor patient prognosis and show that low-dose radiotherapy combined with peposertib effectively abrogates neuroblastoma self-renewal compared to chemotherapy-based regimens, thereby implicating DNA-PKcs as a key mediator of metastatic relapse and supporting radiotherapy plus DNA-PKcs inhibition as a compelling therapeutic strategy for relapsed or refractory high-risk neuroblastoma.

Keywords:  DNA double strand breaks; DNA-PKcs; apoptosis; high risk neuroblastoma; ionizing radiation; topoisomerase II inhibitors

DOI:  https://doi.org/10.1016/j.canlet.2026.218383
Cancer Lett. 2026 Mar 03. pii: S0304-3835(26)00169-2. [Epub ahead of print]645 218406

Targeting ACSS2 disrupts metabolic-epigenetic crosstalk to restore apoptosis and temozolomide chemosensitivity in pancreatic neuroendocrine tumors.

Qin Dang, Liangju Peng, Yinrong Niu, Xuan Pan, Zeng Ye, Ting Wang, Yan Wang, Jiahao Wu, Zheng Li, Heli Gao, Miaoyan Wei, Qiangsheng Hu, Guixiong Fan, Desheng Jing, Junfeng Xu, Shunrong Ji, Xianjun Yu, Xiaowu Xu, Yi Qin.

  Temozolomide (TMZ) based chemotherapy remains the standard frontline treatment for advanced pancreatic neuroendocrine tumors (PNETs). However, the therapeutic efficacy is frequently compromised by primary or acquired resistance, and the underlying mechanisms beyond MGMT expression remain poorly understood. In this study, we identify acetyl coenzyme A synthetase 2 (ACSS2) as a critical driver of TMZ resistance in PNETs through a metabolic epigenetic signaling axis. Integrated single-cell RNA sequencing and clinical cohort analyses reveal that ACSS2 is significantly upregulated in PNETs and positively correlates with a chemoresistant transcriptomic profile. Mechanistically, ACSS2 mediated acetate metabolism facilitates histone hyperacetylation, which directly promotes the transcription of BCL6, a potent transcriptional repressor. BCL6 in turn binds to the promoter of the master tumor suppressor TP53 and silences its expression, thereby bypassing TMZ induced G2/M arrest and suppressing apoptosis. Pharmacological inhibition or genetic ablation of the ACSS2/BCL6 axis restores P53 mediated DNA damage response and re-sensitizes PNET cells to TMZ. Notably, combined treatment with an ACSS2 inhibitor and anti-PD1/L1 immunotherapy demonstrates superior synergistic efficacy in patient derived organoids and immunocompetent Rip1-Tag2 mice. This study delineates a non-redundant metabolic epigenetic barrier to chemotherapy and suggests that targeting the ACSS2/BCL6/P53 axis represents a promising strategy to overcome chemoresistance in PNET patients.

Keywords:  ACSS2; Acetyl-CoA; BCL6; Pancreatic neuroendocrine tumors; TMZ

DOI:  https://doi.org/10.1016/j.canlet.2026.218406
Cancer Lett. 2026 Mar 02. pii: S0304-3835(26)00158-8. [Epub ahead of print] 218395

DysUFMylation reprograms immunosuppressive neutrophils to potentiate anti-PD-1 therapy in hepatocellular carcinoma.

Xukang Gao, Min Xu, Zeping Han, Zhiqiu Hu, Yipeng Su, Guoqiang Sun, Wei Chen, Song Qiu, Shuangjian Qiu, Mien-Chie Hung, Chenhao Zhou, Yong Yi.

  Immune checkpoint blockade has been used to treat transformed hepatocellular carcinoma (HCC), but its clinical benefit remains limited, underscoring the need to elucidate the underlying mechanisms of resistance and predictive biomarkers. Here, we identified that UFL1-mediated UFMylation plays a critical role in remodeling the immune microenvironment of HCC. Low UFL1 expression enhanced CD8+ T-cell infiltration and cytotoxicity while reducing tumor-associated neutrophil (TAN) infiltration and N2-like polarization, which correlated with an improved immunotherapy response. Mechanistically, UFL1 deficiency impaired the stability of PRMT5, thus inhibiting the DNA binding ability of NF-κB p65 and reducing the expression of CXCL8. This led to decreased neutrophil infiltration and N2 polarization, ultimately enhancing the CD8+ T-cell-mediated immune response. Low UFL1 expression synergized with anti-PD-1 therapy to prolong survival in orthotopic and spontaneous HCC models, whereas pharmacologic inhibition of CXCL8-CXCR1/2 signaling using SX-682 recapitulated these effects. Clinically, patients who responded to immunotherapy exhibited reduced UFL1, PRMT5 and CXCL8 expression; decreased neutrophil infiltration; elevated CD8+ T-cell activity; and lower serum CXCL8 levels. These findings reveal a UFL1-PRMT5-NF-κB p65-CXCL8 axis that governs neutrophil-driven immunosuppression and identify CXCL8 as both a predictive biomarker and therapeutic target to optimize immunotherapy in patients with HCC.

Keywords:  DysUFMylation; Hepatocellular carcinoma; Tumor immune microenvironment; Tumor-associated neutrophils; anti-PD-1 therapy

DOI:  https://doi.org/10.1016/j.canlet.2026.218395
Cancer Discov. 2026 Mar 04.

Targeting the lipid metabolism proteins FASN and GPAM in alveolar type II cells decreases lung metastasis.

Xiao-Zheng Liu, Yulia Panina, Weigang Cai, Juan Fernández-García, Yiming Peng-Winkler, Jiadong Mao, Alina Dahlhaus, Hui-Chao Zhou, Ming Liu, Melanie Planque, Johannes Ceuppens, Sebastian Igelmann, Xander Spotbeen, Jakub Idkowiak, Jonas Dehairs, Janine Theile, Konstantinos Axarlis, Kristien Borremans, Josephine Van Cauwenberge, Avinash Ghanate, Josep Tarragó-Celada, Alejandro Suárez-Bonnet, Richard Mitter, Vincen Wu, Paolo Inglese, James S McKenzie, Rory T Steven, Alex Dexter, Bin Yan, Jean-Luc Vorng, Zoltán Takáts, Josephine Bunch, Ian S Gilmore, Peter Carmeliet, Christine Desmedt, Ilaria Malanchi, Johannes V Swinnen, Patricia Altea-Manzano, Kim-Anh Lê Cao, Johannes Meiser, Mariia Yuneva, Sarah-Maria Fendt.

Cancer cells that seed in the lung require lipids often produced by alveolar type II (AT2) cells. However, whether overt metastases depend on AT2 cell-derived lipids and whether AT2 cells can be targeted to reduce metastasis growth remains unknown. We discovered that breast cancer-derived lung metastases stimulate the proliferation of AT2 cells in their vicinity and reprogram them into lipid feeder cells in mice and patients using spatial analysis. Mechanistically, the metastasis secretome activates the transcription factor sterol regulatory element-binding transcription factor 1 (SREBP-1) in AT2 cells, enhancing the expression of key de novo lipid synthesis genes including fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase 1 (GPAM). Deleting Fasn selectively in AT2 cells or targeting FASN and GPAM systemically significantly impairs lung metastasis growth in mice. In summary, we discovered that overt metastases reprogram AT2 cells and that targeting the lipid metabolism of AT2 cells impairs metastasis growth.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0191
Cancer Cell. 2026 Mar 05. pii: S1535-6108(26)00107-8. [Epub ahead of print]

Tumor-restraining fibroblasts emerge after chemotherapy specifically in responders.

Krishnan K Mahadevan, Raghu Kalluri.

In this issue of Cancer Cell, Ma et al. identify a neoadjuvant chemotherapy-induced population of PTGER3+ cancer-associated fibroblasts (CAFs) in patients with bladder cancer.1 These CAFs undergo lipid oxidation reprogramming and enhance CD8+ T cell function, facilitating tumor microenvironment remodeling and restraining tumor progression.

DOI: https://doi.org/10.1016/j.ccell.2026.02.009
Nat Commun. 2026 Mar 06. pii: 1655. [Epub ahead of print]17(1):

Native chromatome profiling reveals hundreds of metabolic enzymes in the nucleus across tissues.

S Kourtis, A Gañez Zapater, C R Elbæk, A Schmidt, R Ghose, A Coll Manzano, L Espinar Calvo, M Guirola, N Pardo-Lorente, M Garcia-Cao, M Pfeiffer, S Haynes, F Fontaine, A Müller, S Sdelci.

Metabolic and epigenetic rewiring are hallmarks of cancer, with increasing evidence suggesting crosstalk between these processes. While previous studies have hinted at the role of metabolic enzymes in the nucleus, the extent and functional relevance of their nuclear localization remain unclear. In this study, we present a comprehensive chromatome proteomic analysis across cancer lineages and healthy samples, revealing that metabolic enzyme moonlighting on chromatin is widespread across various tissues and metabolic pathways. We show that the abundance of metabolic enzymes on chromatin is tissue-specific, with oxidative phosphorylation proteins notably depleted in lung cancer, suggesting a link between nuclear metabolism and cell identity. Further, we explore the dynamic chromatin association of one-carbon folate enzymes, demonstrating their involvement in DNA damage and repair processes. Finally, we asked whether restricting metabolic enzymes to specific subcellular compartments rewires the transcriptome, thereby decoupling the observed transcriptional changes from mere metabolite diffusion. Our findings propose and validate novel non-canonical nuclear roles for several metabolic enzymes, providing new insights into the functional relationship between metabolism and chromatin regulation. This study underscores the hypothesis that the nucleus is populated by metabolic enzymes, offering new avenues for understanding how nuclear metabolism impacts chromatin function and cancer progression.

DOI: https://doi.org/10.1038/s41467-026-69217-2
Cell Rep. 2026 Mar 05. pii: S2211-1247(26)00139-7. [Epub ahead of print]45(3): 117061

Large adipocytes increase vesicle-mediated lipid release and promote breast cancer malignancy.

Garrett F Beeghly, Irina Kopyeva, Jenny Deng, Marlee I Pincus, Rohan R Varshney, Dilip D Giri, Domenick J Falcone, Michael C Rudolph, Marc A Antonyak, Neil M Iyengar, Claudia Fischbach.

  Primary adipocytes exhibit striking variability in size, yet the functional consequences of adipocyte hypertrophy remain unclear due to insufficient experimental approaches to control for cell size. Here, we establish methods to culture large and small primary adipocytes isolated from the same adipose depot, enabling size-resolved analyses independent of systemic obesity. Using transcriptomic, lipidomic, and functional profiling across two mouse models of obesity, as well as human clinical samples, we show that adipocyte size-rather than body weight-drives distinct phenotypic cell states. Notably, large adipocytes increase extracellular vesicle-mediated lipid release. In coculture assays, this shift enhances lipid uptake, migration, and proliferation of breast cancer cells through fatty acid oxidation. Consistent with these findings, individuals with larger mammary adipocytes exhibit elevated fasting triglycerides independent of body mass index. Together, our results identify adipocyte size as a key determinant of adipose tissue function with implications for both metabolic disease and cancer progression.

Keywords:  CP: cancer; CP: metabolism; adipocyte; adipose tissue; breast cancer; extracellular vesicles; hypertrophy; lipid metabolism; obesity; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2026.117061