bims-meract 2026-06-14 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–06–14
seventeen papers selected by
Andrea Morandi, Università degli Studi di Firenze

SERPINE2-mediated activation of JAK2/STAT3 facilitates NRF2 nuclear translocation and GCLC transcription to confer ferroptosis resistance and lenvatinib resistance in hepatocellular carcinoma.
Targeting ATF3-mediated asparagine biosynthesis reverses acquired resistance to KRASG12C inhibitors.
SLC16A9-Mediated Carnitine Uptake Enhances Radiotherapy Resistance in Colorectal Cancer via Lipid Metabolic Reprogramming.
Oncometabolite 2-hydroxyglutarate destabilizes CDH1 to regulate quiescence and enhance chemotherapy sensitivity.
PHGDH loss promotes hypoxia tolerance through glycolytic reprogramming and enhanced HIF-1 activity.
Organelle proteomics reveals novel metabolic vulnerabilities in FLT3-ITD cells.
Targeting Lactate-Driven Stromal Autophagy via MCT1 Disrupts the Immunosuppressive Niche and Sensitizes Pancreatic Cancer to PD-1 Blockade.
Tumor cells metabolically resist immune-checkpoint therapy by macrophage efferocytosis-mediated fatty acid recycling.
Lactate-mediated cholesterol uptake promotes liver cancer progression via the SCARB1-autophagy axis.
Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming.
WNK4 Enhances Anti-PD-1 Resistance and Promotes Tumor Progression in Hepatocellular Carcinoma by Reprogramming Cysteine Metabolism in Cancer-Associated Fibroblasts.
Inflammatory cytokines induce new cancer dependencies.
Inhibition of 5'-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.
RNF138 promotes cisplatin resistance and PD-L1-mediated immune evasion via JAK2/STAT3 activation in nasopharyngeal carcinoma.
Synergistic dual targeting of mTOR and GLS1 overcomes glutamine-driven resistance in triple-negative breast cancer.
Hp1bp3 loss links chromatin reorganization to metabolic vulnerability in glioma.
SHLD2 loss is a synthetic vulnerability to Polθ inhibition combined with radiotherapy.

J Exp Clin Cancer Res. 2026 Jun 06.

SERPINE2-mediated activation of JAK2/STAT3 facilitates NRF2 nuclear translocation and GCLC transcription to confer ferroptosis resistance and lenvatinib resistance in hepatocellular carcinoma.

Kan Liu, Shenglan Huang, Yongkang Xu, Ye Mao, Ning Chen, Yixin Yuan, Qinwen Xiao, Shumin Fu, Jianbing Wu.

   BACKGROUND: Acquired resistance remains a major obstacle in molecular-targeted therapy for advanced hepatocellular carcinoma (HCC). This study aimed to elucidate the role and underlying mechanisms of SERPINE2 in mediating lenvatinib resistance by suppressing ferroptosis.
METHODS: We analyzed SERPINE2 expression and its clinical prognostic relevance using public databases (TCGA) and clinical samples (tumor tissues and serum) from patients with HCC treated with lenvatinib. By establishing hypoxic and acquired lenvatinib-resistant HCC cell models, combined with subcutaneous xenograft and orthotopic liver cancer mouse models, we systematically evaluated the functional role of SERPINE2 in tumor proliferation, apoptosis, ferroptosis, and lenvatinib resistance in vitro and in vivo. Mechanistic insights were obtained through transcriptome sequencing (RNA-seq), quantitative proteomics, co-immunoprecipitation (Co-IP), nuclear-cytoplasmic fractionation, and measurement of key ferroptosis indicators (lipid ROS, mitochondrial membrane potential, and transmission electron microscopy). Finally, we assessed the therapeutic potential of targeted interventions combining a JAK inhibitor (Ruxolitinib) or NRF2 inhibitor (ML385) with lenvatinib to overcome resistance in vitro and in vivo.
RESULTS: SERPINE2 was markedly upregulated in hypoxic and lenvatinib-resistant HCC models and clinical tissues, correlating with a poor prognosis. Mechanistically, SERPINE2 activates the JAK2/STAT3 signaling pathway, promotes the STAT3-NRF2 interaction, and facilitates NRF2 nuclear translocation. This upregulates the antioxidant enzyme GCLC, which strengthens glutathione synthesis, inhibits lipid peroxidation and ferroptosis, and ultimately confers lenvatinib resistance. Inhibiting SERPINE2, STAT3, or GCLC restored ferroptosis and re-sensitized HCC cells to lenvatinib. Furthermore, the combination treatments exhibited significant synergistic antitumor effects in vitro and in vivo. Clinically, elevated SERPINE2 levels positively correlated with GCLC, predicted worse survival outcomes, and effectively distinguished lenvatinib-resistant patients.
CONCLUSIONS: This study established the SERPINE2-JAK2/STAT3-NRF2-GCLC signaling axis as a key mechanism driving ferroptosis resistance and lenvatinib treatment failure. Targeting this axis provides a novel therapeutic strategy for overcoming lenvatinib resistance in HCC.

Keywords:  Ferroptosis; GCLC; Hepatocellular carcinoma; Lenvatinib resistance; SERPINE2; STAT3

DOI:  https://doi.org/10.1186/s13046-026-03746-y
Oncogene. 2026 Jun 10.

Targeting ATF3-mediated asparagine biosynthesis reverses acquired resistance to KRASG12C inhibitors.

Yanjing Zhu, Chi Zhang, Min Li, Luoyan Ai, Fan Xu, Yiyi Yu, Shan Yu, Xiaojing Xu, Qing Liu, Mengxuan Zhu, Mengling Liu, Jingyuan Wang, Yutong Liu, Zhenghang Xu, Haojie Zhou, Huishan Li, Rui Wu, Ke Peng, Tianshu Liu.

Despite substantial advances in targeting KRASG12C, tumor acquired resistance to KRASG12C inhibitors (KRASG12Ci) remains a major barrier to progress. Here, we report ATF3-driven asparagine metabolic reprogramming as a key convergence point of KRASG12Ci resistance. Multi-omics profiling of resistant models revealed a chronic activation of the integrated stress response (ISR) and a concomitant upregulation of asparagine synthesis. We found that the ISR-inducible transcription factor ATF3 was upregulated and directly transactivated asparagine synthetase (ASNS), driving asparagine production. Genetic ablation of ATF3 or ASNS restored KRASG12Ci sensitivity, whereas exogenous asparagine reconstituted resistance. This ATF3-ASNS axis was conserved in the patient-derived model of acquired KRASG12Ci resistance. Furthermore, pharmacological inhibition of the upstream ISR kinase PERK synergized with KRASG12Ci to overcome resistance. This study reveals a therapeutically targetable mechanism of asparagine metabolic reprogramming that facilitates KRASG12C inhibitor resistance.

DOI: https://doi.org/10.1038/s41388-026-03838-1
Compr Physiol. 2026 Jun;16(3): e70184

SLC16A9-Mediated Carnitine Uptake Enhances Radiotherapy Resistance in Colorectal Cancer via Lipid Metabolic Reprogramming.

Meng Wang, Jian Tang, Xing Wen, Jianhui Gu, Jie Zhang, Yuanchuan Zhang, Liping Wu.

   BACKGROUND: Radiation resistance severely impairs the therapeutic efficacy of radiotherapy in colorectal cancer (CRC). Lipid metabolic reprogramming, particularly the activation of fatty acid oxidation (FAO), has been well recognized to be closely implicated in radioresistance, whereas its underlying regulatory mechanism remains poorly elucidated. This study aimed to explore the functional role of the transporter SLC16A9 in CRC radioresistance and its correlation with carnitine metabolism as well as the FAO signaling pathway.
METHODS: Differentially expressed genes associated with radioresistance were screened by analyzing public transcriptomic databases and further validated using clinical specimens. CCK-8 assay, colony formation assay, comet assay, and cell apoptosis analysis were performed to evaluate cellular radiosensitivity. RT-qPCR, Western blot, and immunofluorescence staining were adopted to detect SLC16A9 expression levels and DNA damage status. Metabolic flux analysis, ATP measurement, and radioactive carnitine uptake assay were utilized to assess carnitine uptake capacity and FAO activity. A nude mouse xenograft tumor model was constructed to determine the in vivo influence of SLC16A9 on tumor response to radiotherapy.
RESULTS: Elevated expression of SLC16A9 was observed in radioresistant CRC cell lines and clinical samples. SLC16A9 facilitated carnitine uptake and augmented FAO pathway activity, which was accompanied by reduced radiation-induced DNA damage, decreased reactive oxygen species (ROS) levels, and enhanced cellular survival capability. Inhibition of FAO partially reversed the above biological effects. In the in vivo model, upregulated SLC16A9 was correlated with attenuated tumor suppression efficacy of radiotherapy, while SLC16A9 inhibition markedly elevated radiosensitivity.
CONCLUSION: SLC16A9 contributed to the development of CRC radioresistance by promoting carnitine uptake and enhancing FAO activity. This study provided novel evidence supporting the association between metabolic reprogramming and radiosensitivity and suggested that targeting SLC16A9 or the FAO pathway held promising potential for clinical therapeutic application.

Keywords:  SLC16A9; carnitine; colorectal cancer; fatty acid oxidation; lipid metabolic reprogramming; radioresistance

DOI:  https://doi.org/10.1002/cph4.70184
Cell Commun Signal. 2026 Jun 10.

Oncometabolite 2-hydroxyglutarate destabilizes CDH1 to regulate quiescence and enhance chemotherapy sensitivity.

Hai-Hui Zhang, Xiang-Tian Chen, Si-Qi Li, Xin-Lei Yan, Meng Wang, Yan Lin, Yi-Yuan Yuan, Yun-Zi Mao, Jie Liu, Wei Xu.

Isocitrate dehydrogenase 1 mutation IDH1R132H generates the oncometabolite (R)-2-hydroxyglutarate (2-HG). However, the mechanisms underlying the better clinical outcomes in patients with IDH1 mutation remain elusive. Here, we report that 2-HG sensitizes chemotherapy by destabilizing Fizzy And Cell Division Cycle 20 Related 1(CDH1) and reducing the number of quiescent cells (G0 phase cells). IDH1R132H-harboring glioblastoma tissues have decreased CDH1, which can be induced by IDH1R132H overexpression or 2-HG treatment in U87MG cells. Mechanistically, 2-HG inhibits Prolyl Hydroxylase Domain-containing protein 1 (PHD1), which hydroxylates proline 431 of CDH1 to maintain its stability. 2-HG induces hypo-hydroxylation of CDH1, rendering it susceptible to CDK1-mediated phosphorylation at serine 151/163, followed by β-TrCP-mediated ubiquitination and proteasomal degradation. Notably, in vitro and in vivo experiments demonstrate that 2-HG induces CDH1 downregulation and reduces quiescent cell populations not only in glioblastoma cells but also in lung cancer and colorectal cancer cells, and consistently sensitizes tumor cells to chemotherapy. Our findings shed light on why IDH1 mutations correlate with better prognosis and highlight the translational potential of 2-HG as a chemotherapy sensitizer.

DOI: https://doi.org/10.1186/s12964-026-02988-9
Cell Death Discov. 2026 Jun 10.

PHGDH loss promotes hypoxia tolerance through glycolytic reprogramming and enhanced HIF-1 activity.

Eduard Petrosyan, Louise A W Martin, Isabelle Legge, John Walsby-Tickle, Adam C Sedgwick, Mark A Hill, James S O McCullagh, Monica M Olcina, Ester M Hammond.

Radiotherapy is widely used in the treatment of lung cancer; a number of intrinsic and extrinsic mechanisms of resistance exist, including hypoxia. Targeting metabolic pathways that support redox homeostasis has been proposed as a strategy to enhance radiosensitivity. The serine synthesis pathway enzyme, phosphoglycerate dehydrogenase (PHGDH), has been implicated in resistance to several anticancer therapies; however, its role in radiotherapy response is poorly defined. We show that PHGDH expression positively correlates with established hypoxia gene expression signatures in lung adenocarcinoma and squamous cell carcinoma patient datasets and is induced under hypoxia (<0.1% O2) in lung cancer cell lines. Hypoxic induction of PHGDH appears mediated by both HIF-1 and PERK signalling, linking PHGDH regulation to hypoxia and the unfolded protein response. Using CRISPR-Cas9 PHGDH knockout models, we demonstrate that loss of PHGDH does not enhance radiosensitivity in normoxia or hypoxia when extracellular serine and glycine are available at physiological or supraphysiological concentrations. Radiosensitisation is observed only under complete serine/glycine deprivation. Unexpectedly, PHGDH loss confers increased tolerance to hypoxic stress, associated with elevated glycolytic flux, increased lactate production, accelerated HIF-1α stabilisation and enhanced expression of hypoxia-inducible genes. Overall, these data indicate that targeting PHGDH alone is unlikely to impact radioresistance in lung cancer under physiologically relevant nutrient conditions and may instead promote metabolic adaptation to hypoxia. This highlights the importance of microenvironmental context when evaluating metabolic targets for combination with radiotherapy.

DOI: https://doi.org/10.1038/s41420-026-03194-9
Leukemia. 2026 Jun 09.

Organelle proteomics reveals novel metabolic vulnerabilities in FLT3-ITD cells.

Valeria Bica, Anna Francesca Pacilè, Martin Boettcher, Valentina Marano, Veronica Marabitti, Francesca Nazio, Mirko Cortese, Thomas Fischer, Livia Perfetto, Dimitrios Mougiakakos, Giorgia Massacci, Francesca Sacco.

In acute myeloid leukemia (AML), the insertion site of internal tandem duplications (ITDs) within the FLT3 gene critically determines the sensitivity to tyrosine kinase inhibitors (TKIs). Despite recent advances, patients harboring ITDs in the tyrosine kinase domain (TKD) still lack effective therapeutic options. To elucidate the molecular basis underlying the differential TKI sensitivity of FLT3-ITD cells, we integrated high-resolution mass spectrometry-based (phospho)proteomics with subcellular fractionation. Our analysis revealed that midostaurin induces the subcellular redistribution of approximately 2500 proteins involved in crucial biological processes, including cell cycle control, autophagy, and metabolism. Functional analyses further demonstrated that the ITD insertion site determines the autophagy response to midostaurin and modulates mitochondrial metabolism, influencing organelle architecture and ATP production, even at steady state. Importantly, by integrating subcellular proteomic dataset with functional metabolic assays, we uncovered a lipid-dependent vulnerability of FLT3-ITD cells: lipid restriction enhances FLT3 trafficking to the plasma membrane, and markedly reduces cell viability, restoring midostaurin sensitivity of resistant FLT3-ITD cells. Together, our findings reveal that the FLT3-ITD insertion site orchestrates a coordinated remodeling of subcellular protein organization, autophagy, and metabolism, and identify lipid-mediated control of FLT3 compartmentalization as a therapeutically actionable mechanism to overcome TKI resistance in FLT3-ITD AML.

DOI: https://doi.org/10.1038/s41375-026-03000-6
Adv Sci (Weinh). 2026 Jun 09. e76008

Targeting Lactate-Driven Stromal Autophagy via MCT1 Disrupts the Immunosuppressive Niche and Sensitizes Pancreatic Cancer to PD-1 Blockade.

Wenfeng Zhuo, Rong Hu, Yuhang Hu, Ping Hu, Shengbo Han, Guozheng Lv, Zhu Zeng, Yong Zhao, Yang Li, Yan Huang, Yingsong Zhao, Hongda Wang, Guangyu Zhao, Eryang Zhao, Gang Zhao.

  Lactate reshapes the tumor microenvironment (TME) through complex communication between cancer and stromal cells. However, it remains undefined whether lactate mediates the interaction between pancreatic cancer (PC) cells and pancreatic stellate cells (PSCs), a significant TME component driving tumorigenesis. This study elucidates the metabolic crosstalk between PC cells and PSCs underlying lactate-driven tumor progression. Our findings demonstrate that PC cells serve as the primary lactate source in the TME, where lactate induces PSC activation through an autophagy-dependent mechanism mediated by protein lactylation. This activation cascade subsequently upregulates programmed cell death-1 (PD-1) expression in CD8+ T cells, promoting immune evasion. Notably, AZD3965, a specific MCT1 inhibitor, sensitizes orthotopic PC to PD-1 blockade, effectively inhibiting tumor development. Mechanistically, MCT1-mediated lactate influx activates PSCs by inducing lactylation of lysine residues K356 and K781 on Vps34, a key autophagy regulator. Moreover, activated PSCs secrete CXCL9/CXCL10, which upregulates PD-1 expression in CD8+ T cells via the CXCR3/STAT3 pathway. This study establishes lactate as a crucial TME signaling molecule orchestrating PSC activation and an immunosuppressive microenvironment, providing compelling evidence for combining MCT1 inhibition with immune checkpoint blockade for pancreatic cancer.

Keywords:  PD‐1; autophagy; lactate; monocarboxylate transporter 1; pancreatic cancer; pancreatic stellate cells

DOI:  https://doi.org/10.1002/advs.76008
Cancer Cell. 2026 Jun 08. pii: S1535-6108(26)00250-3. [Epub ahead of print]44(6): 1235-1254.e11

Tumor cells metabolically resist immune-checkpoint therapy by macrophage efferocytosis-mediated fatty acid recycling.

Zhixian Liang, Xiaohang Long, Zhewen Xiong, Patrick Pak-Chun Wong, Siyuan Huang, Siyun Chen, Yiling Zhang, Lingyun Zhang, Chunning Leung, Jianquan Cao, Haoran Wu, Hui Yue, Zihui Zhao, Yalin Tu, Baoyi Yin, Weiqin Yang, Jing Wang, Shufen Chen, Xuerao Zhang, Yuk Wah Tsang, Chengpeng Zhong, Xiaoyu Liu, Lipeng Ding, Jiahuan Lu, Willis Wai-Yiu Si-Tou, Yan Liu, Yaxian Wang, Yingnan Lin, Jianxin Liang, Weida Ren, Joaquim Si-Long Vong, Man Tong, Xiaoyu Tian, Hannah Xiaoyan Hui, Jingying Zhou, Saiming Ngai, Shelly Ni, Ka-Fai To, Thomas Braun, Joseph Jao-Yiu Sung, Stephen Lam Chan, Alfred Sze-Lok Cheng.

  Tumor cells metabolically adapt to the nutrient-deprived tumor microenvironment (TME). However, the metabolic plasticity underlying immune-checkpoint blockade (ICB) adaptation remains unclear. Here, we report that tumor cells exploit macrophage efferocytosis to metabolically counteract immune-checkpoint targeting. Serial tumor biopsies from patients with ICB-resistant hepatocellular carcinoma (HCC) demonstrate heightened tumor cell fatty acid uptake (FAU) with concomitant up-regulation of TREM2+ lipid-associated macrophages (LAMs) in lipid-laden TME. Myeloid-specific Trem2 deficiency and anti-TREM2 antibody abolish fatty acid-dependent energy production in ICB-resistant tumor cells, resensitizing them to ICB via epigenetic TME remodeling. Mechanistically, TREM2+ LAMs recycle fatty acids to tumor cells via efferocytosis-derived extracellular vesicles, thereby promoting H3K36 acetylation-associated activation of MYC and TGF-β signaling. Single-cell spatial analysis supports TREM2+ LAM efferocytosis in the epigenetic immune evasion of patients with ICB-resistant HCC. As high TREM2+ LAMs correlate with FAU and ICB non-responsiveness in multiple human cancers, our study identifies a common metabolic vulnerability for combinatorial immune-checkpoint targeting.

Keywords:  TREM2; efferocytosis; fatty acid metabolism; hepatocellular carcinoma; immune-checkpoint blockade; lipid-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2026.05.005
EMBO Rep. 2026 Jun 10.

Lactate-mediated cholesterol uptake promotes liver cancer progression via the SCARB1-autophagy axis.

Jiamin Chen, Mingyue Zhao, Guanxu Ji, Kecheng Liu, Shengqi Shen, Shi-Ting Li, Jin Cai, Linchong Sun, Jin Li, Ping Gao, Tong Zhang.

Metabolic reprogramming, including enhanced glycolysis and altered fatty acid metabolism, supports the proliferation of cancer cells under hypoxic stress. However, the mechanism underlying the regulation of cholesterol metabolism under hypoxic stress remains incompletely understood. Here, we report that lactate-induced cholesterol accumulation activates mammalian target of rapamycin complex 1 (mTORC1) signalling under hypoxic conditions, thereby promoting hepatocellular carcinoma (HCC) progression. Mechanistically, lactate upregulates scavenger receptor class B type 1 (SCARB1) expression by increasing histone H3 lysine 18 lactylation (H3K18la), leading to increased cholesterol levels. We further demonstrate that SCARB1-mediated cholesterol uptake is essential for the activation of mTORC1, which promotes tumour growth by preventing excessive autophagy in HCC cells. Importantly, analysis of clinical HCC samples reveals a positive correlation between H3K18la expression and SCARB1 expression. Taken together, these findings provide novel insights into hypoxia-driven metabolic reprogramming and reveal a previously unrecognized connection between lactate and cholesterol metabolism, suggesting a potential innovative cancer therapy for HCC.

DOI: https://doi.org/10.1038/s44319-026-00829-x
Nat Commun. 2026 Jun 11.

Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming.

Liang Shi, Boqiang Liu, Ruya Sun, Jing He, Hao Shen, Weiqi Li, Yi Wang, Weijun Zhao, Chenqi Jin, Binghan Jin, Yuanshi Tian, Lingfeng Ma, Lidan Hou, Mingyu Chen, Jiaying Shen, Bo Shen, Xiao Liang, Hong Yu, Yifan Wang, Di Wang, Xiujun Cai.

Tumor evolution enables liver cancer cells to acquire survival advantages and evade therapy-induced cell death. However, the role of natural killer (NK) cells in liver cancer evolution remains unclear. Here, we establish immune-humanized spatiotemporal liver cancer models and integrate single-cell, spatial transcriptomic, and CRISPR/Cas9 screening analyses to investigate this process. We demonstrate that early NK cell-mediated immunosurveillance promotes tumor cell state transition and impairs subsequent adaptive immune responses. Mechanistically, NK cells induce lipid metabolic reprogramming, particularly cholesterol accumulation, and enhance tumor stemness, both of which promote liver cancer evolution. Furthermore, combined anti-LAG-3 treatment and liver X receptor activation suppress tumor evolution and improve the efficacy and durability of immune checkpoint blockade in advanced liver cancer. Collectively, our findings identify that NK cell-mediated early immunosurveillance promotes liver cancer evolution and suggest immunometabolic therapy as a potential strategy for advanced liver cancer.

DOI: https://doi.org/10.1038/s41467-026-74360-x
FASEB J. 2026 Jun 15. 40(11): e71990

WNK4 Enhances Anti-PD-1 Resistance and Promotes Tumor Progression in Hepatocellular Carcinoma by Reprogramming Cysteine Metabolism in Cancer-Associated Fibroblasts.

Ge Yu, Yun-Long Cui, Han Mu, Dong-Ming Liu, Xu Bao, Hong-Yuan Zhou, Hui-Kai Li.

  Hepatocellular carcinoma (HCC) is the most prevalent subtype of primary liver cancer. Immunotherapy, particularly targeting immune checkpoints such as programmed cell death protein 1 (PD-1), has shown considerable therapeutic promise. Bioinformatic analysis of Gene Expression Omnibus datasets demonstrated significant upregulation of WNK lysine deficient protein kinase 4 (WNK4) expression in HCC tissues obtained from untreated patients or anti-PD-1 non-responders, suggesting a potential role for WNK4 in HCC progression and immunotherapy resistance. Through a series of experiments, we confirmed that WNK4 promoted the proliferative and migrative abilities of HCC cells and enhanced the resistance of HCC model mice to anti-PD-1 therapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), critically influences immunotherapy efficacy. The current study uncovered that WNK4 was transferred by HCC cell-derived exosomes into CAFs and promoted the cysteine metabolic reprogramming. Moreover, WNK4-mediated promotional effects of CAFs on the malignant phenotypes of HCC cells and anti-PD-1 resistance were in a cysteine-dependent manner. According to mechanism investigation, WNK4 could bind high mobility group box 1 (HMGB1) and induce its phosphorylation and cytoplasmic retention, thus reducing nuclear HMGB1-p53 interaction to enhance cystathionine gamma-lyase (CTH) expression. In summary, this study unveils a novel WNK4-HMGB1-p53 axis in CAFs that promotes HCC progression and modulates cysteine metabolism to foster immunotherapy resistance, offering potential therapeutic targets for HCC.

Keywords:  WNK lysine deficient protein kinase 4; anti‐PD‐1 resistance; cancer‐associated fibroblasts; exosome; hepatocellular carcinoma

DOI:  https://doi.org/10.1096/fj.202502777R
Nat Genet. 2026 Jun;58(6): 1353-1367

Inflammatory cytokines induce new cancer dependencies.

Collins K Cheruiyot, Sarah Y Kim, Juan Dubrot, Sarah K Lane-Reticker, Alex Miranda, Ashwin V Kammula, Jonathan J Perera, Peter P Du, Cun Lan Chuong, Rachel A Fetterman, Nelson H Knudsen, Aiping Jiang, Juliette S M T Suermondt, Lomax F Pass, Cong Fu, Meng-Ju Wu, Lei Shi, Seth Anderson, Audrey J Muscato, Omar I Avila, Ian C Kohnle, Emily A Kessler, Hans W Pope, Sarah G Noel, Kira E Olander, Jooho Chung, Kayla J Colvin, Nabeel Bardeesy, Kathleen B Yates, Robert T Manguso.

Tumor cells respond and adapt to environmental stresses that facilitate growth in hostile environments, including cytokine-mediated inflammation elicited by antitumor immunity and enhanced by immune checkpoint blockade (ICB). However, cytokine responses also induce transcriptional and cell-state changes that may predispose tumor cells to new vulnerabilities, which remain poorly explored. Here we performed in vitro genome-scale CRISPR loss-of-function screens in eight cancer models exposed to interferon-γ (IFNγ), interferon-β or tumor necrosis factor to map inflammation-induced genetic vulnerabilities. We identified members of the glycosylphosphatidylinositol (GPI) transamidase complex and the lipid phosphatase FITM2 as interferon-specific cancer dependencies. Tumor-specific deletion of GPI transamidase subunits or FITM2 markedly enhanced response to ICB in vivo. By integrating functional genomics, metabolomics and pharmacologic perturbation of downstream stress pathways, we found that loss of FITM2 predisposed cancer cells to IFNγ-driven endoplasmic reticulum and oxidative stress, culminating in paraptosis-like cell death. Collectively, these findings identify tumor-intrinsic dependencies governing responses to inflammatory cytokines.

DOI: https://doi.org/10.1038/s41588-026-02614-x
J Exp Clin Cancer Res. 2026 Jun 13.

Inhibition of 5'-tiRNAGly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.

Xinliang Gu, Yu Zhang, Yang Li, Xun Li, Yuening Sun, Shuo Ma, Xinyue Qin, Yuejiao Huang, Xianjuan Shen, Ming Zheng, Quanhua Yi, Zhiyuan Tang, Shaoqing Ju.

   BACKGROUND: Transfer RNA-derived small RNAs (tsRNAs) have been implicated in tumor progression and immune regulation in recent years. However, the specific role of tRNA halves (tiRNAs), a subclass of tsRNAs, in modulating immunotherapy response remains unexplored.
METHODS AND RESULTS: In this study, 5'-tiRNAGly levels were examined in gastric cancer (GC) patients and found to be upregulated, especially in non-responders to anti-PD-1 therapy. Elevated 5'-tiRNAGly levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5'-tiRNAGly bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5'-tiRNAGly restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5'-tiRNAGly was found to decrease the activity of α-ketoglutarate dehydrogenase and inhibit succinylation of histone H3 at lysine 79 (H3K79suc), thereby downregulating PD-L1 transcription and reducing therapeutic responsiveness to PD-1 inhibitors. Conversely, restoration of this epigenetic modification upon 5'-tiRNAGly inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy.
CONCLUSION: Our findings indicate that targeting 5'-tiRNAGly may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients.

Keywords:  Gastric cancer; Glutamine metabolism; OGDHL; PD-1; Succinylation; tRNA-derived small RNAs

DOI:  https://doi.org/10.1186/s13046-026-03758-8
Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00625-X. [Epub ahead of print]45(6): 117547

RNF138 promotes cisplatin resistance and PD-L1-mediated immune evasion via JAK2/STAT3 activation in nasopharyngeal carcinoma.

Chuyu He, Liming Lou, Yuan Lei, Xianhui Wen, Daofeng Huang, Haibin Lai, Jiachen Huang, Lewei Zhou, Qianqian Zhang, Jun Ma, Yelin Liang, Han Qiao, Yuan Zhang.

  Chemoresistance is a primary factor limiting nasopharyngeal carcinoma (NPC) treatment. Growing evidence indicates that E3 ubiquitin ligases play a pivotal role in chemoresistance. Here, we identified that the E3 ubiquitin ligase RNF138 is significantly upregulated in NPC patients who do not respond to chemotherapy. Our study reveals that RNF138 promotes the K48-linked ubiquitination of hnRNPA0 at K133, thereby destabilizing WWOX mRNA. The subsequent loss of WWOX protein relieves the inhibition of JAK2 self-phosphorylation, leading to constitutive pathway activation. Consequently, RNF138-JAK2/STAT3 activation suppresses chemotherapy-induced apoptosis via reduced ROS production and promotes immune evasion by upregulating PD-L1. Clinically, high RNF138 expression correlated with poor prognosis and resistance to chemotherapy. In conclusion, this study unveils the RNF138-hnRNPA0-WWOX axis as a driver of JAK2/STAT3 activation, leading to both chemoresistance and immune evasion in NPC. This work positions RNF138 as a valuable biomarker to guide individualized chemotherapy, and highlights JAK inhibitors as a potential targeted therapy for NPC patients.

Keywords:  CP: cancer; JAK2/STAT3 pathway; RNF138; chemoresistance; immune evasion; nasopharyngeal carcinoma

DOI:  https://doi.org/10.1016/j.celrep.2026.117547
Pharmacol Res. 2026 Jun 11. pii: S1043-6618(26)00210-0. [Epub ahead of print]230 108295

Synergistic dual targeting of mTOR and GLS1 overcomes glutamine-driven resistance in triple-negative breast cancer.

Mengting Lyu, Liushun Wu, Yin Li, Yang Yu, Ying Li, Tongsheng Wang, Feng-Qing Xu, Deling Wu, Wuxi Zhou.

  Resistance to therapeutic agents represents a critical barrier in the clinical management of triple-negative breast cancer (TNBC), necessitating novel therapeutic strategies. We discovered that mammalian target of rapamycin (mTOR) and glutaminase 1 (GLS1) mediated glutamine metabolism-a TNBC-addicted process-critically drives aggressive proliferation and confers therapeutic resistance. The combined treatment with rapamycin (an mTOR inhibitor) and CB839 (a GLS1 inhibitor) elicited synergistic anti-tumor effects in diverse TNBC cell lines. This synergy arose from‌ inhibition of metabolic rewiring, ‌characterized by‌ perturbations in adenosine triphosphate (ATP) homeostasis, redox equilibrium, metabolite pools, and signaling cascades, ‌ultimately triggering multimodal‌ cell death mechanisms. Furthermore, ‌synergistic‌ pharmacological inhibition of mTOR and GLS1 ‌significantly suppressed‌ in vivo tumor growth and metastasis ‌in murine models‌, ‌with no overt toxic effects observed‌. Overall, our findings indicate dual inhibition of mTOR and GLS1 as a promising clinical strategy to counteract glutamine-driven resistance, enhancing therapeutic efficacy in TNBC.

Keywords:  GLS1 inhibitor; Synergistic effects; Triple-negative breast cancer; mTOR inhibitor

DOI:  https://doi.org/10.1016/j.phrs.2026.108295
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2601061123

Hp1bp3 loss links chromatin reorganization to metabolic vulnerability in glioma.

Brittney Lozzi, Taylor A Gatesman, Pushan Dasgupta, Debosmita Sardar, Yeunjung Ko, Chenyu Mao, Hsiao-Chi Chen, Rachel N Curry, Dongjoo Choi, Carrie A Mohila, Melissa L Bondy, Ganesh Rao, Marco Gallo, Sameer Agnihotri, Benjamin Deneen.

  High-grade gliomas (HGGs) are aggressive brain tumors with poor prognosis, driven in part by metabolic and epigenetic adaptations. Methionine metabolism supports HGG growth by supplying S-adenosylmethionine for methylation reactions, yet how nutrient availability influences chromatin organization in HGG remains incompletely understood. Using an immunocompetent mouse model of HGG, we found that dietary methionine restriction reduced tumor proliferation, extended survival, and induced partial nuclear inversion. We identified Hp1bp3 as a key regulator of tumor growth that functions by interacting with nuclear tethering proteins to mediate chromatin reorganization. Loss of Hp1bp3 results in the upregulation of histone demethylases leading to selective depletion of H3K9me3-marked heterochromatin and accelerated glioma growth. Combining methionine restriction with Hp1bp3 loss increased the frequency of partial nuclear inversion and further suppressed tumor progression. These findings identify Hp1bp3 as a chromatin regulator linking methionine metabolism to heterochromatin stability and suggest that dietary methionine modulation can influence the structural organization of chromatin to slow tumor growth in HGG.

Keywords:  dietary restriction; epigenetics; glioma; methionine; nuclear organization

DOI:  https://doi.org/10.1073/pnas.2601061123
Sci Adv. 2026 Jun 12. 12(24): eaeb4508

SHLD2 loss is a synthetic vulnerability to Polθ inhibition combined with radiotherapy.

Gonzalo Rodriguez-Berriguete, Purusotha Thambiayah, Alessandro Cicconi, Nicole Machado, Celia Gotorbe, David Nderitu, Wei-Chen Cheng, Gerissa Fowler, Marie Laure Boursier, Aurora Cerutti, Vera Grinkevich, Bethany Rebekah Hill, Katjuša Koler, Sophie Alice Langdon, Jayesh B Majithiya, Suraj Menon, Shaun Moore, Joana Neves, Natalie M Palmer-Deverill, Eeson Rajendra, Marina Roy-Luzarraga, Asmita Thapa, Robert A Heald, Graeme C M Smith, Helen M R Robinson, Marco Ranzani, Geoff S Higgins.

Inhibition of DNA polymerase theta (Polθ), an essential enzyme for repairing DNA double-strand breaks (DSBs) via microhomology-mediated end joining (MMEJ), has proven to be an exquisitely effective monotherapy in HR-deficient tumor models. In addition, Polθ inhibition (Polθi) can induce tumor-selective radiosensitization, but unlike its monotherapy use, no clinically actionable biomarkers have yet been identified to predict this effect. Here, we profiled 54 cancer cell lines and found that Polθi induces substantial radiosensitization in most models, although with marked variability not explained by indicators of Polθ activity. To pinpoint molecular determinants of radiosensitization by Polθi, we performed a CRISPR knockout screen which revealed loss of the TP53BP1/Shieldin pathway component SHLD2 (FAM35A) as a vulnerability to Polθi combined with RT. We found that SHLD2 is deleted in a subset of human prostate cancers, frequently alongside PTEN loss, an adverse prognostic factor. We demonstrated that SHLD2 loss not only increases sensitivity to RT alone, as reported previously, but also enhances the radiosensitizing effect of Polθi, independently of PTEN status and without requiring HR deficiency. Moreover, our findings support a model in which SHLD2 deficiency increases Polθ dependence following RT, with Polθ activity limiting DSB accumulation and chromosomal instability, via a compensatory mechanism independent of canonical MRE11/CtIP-mediated DNA end resection. In summary, we found that SHLD2 loss is a collateral vulnerability that can be exploited through combined treatment with Polθi and RT.

DOI: https://doi.org/10.1126/sciadv.aeb4508