bims-meract Biomed News
on Metabolic reprogramming and anti-cancer therapy
Issue of 2026–04–05
sixteen papers selected by
Andrea Morandi, Università degli Studi di Firenze
  1. Metabolic Response to CDK4/6 Inhibition in ER+ Breast Cancer Creates a Therapeutic Vulnerability in Drug-Tolerant Persister Cells.
  2. PSAT1 Promotes NSCLC Progression via the De Novo Serine Synthesis Pathway and Represents a Therapeutic Vulnerability.
  3. Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.
  4. Regulation of mitochondrial ROS by C15ORF48 in a basal cell subpopulation contributes to chemotherapy resistance in TNBC.
  5. LDHA-driven lactate metabolism promotes MDSC activation and immunosuppressive microenvironment in prostate cancer.
  6. Fatty Acid Synthase (FASN) as a targeted therapeutic in acquired 5-fluorouracil resistance in pancreatic cancer.
  7. Targeting the noncanonical function of metabolic enzyme PHGDH in driving PD-L1 expression and cancer immune evasion.
  8. Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.
  9. NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.
  10. PTEN loss drives B7H3 upregulation via the mTORC2/FOXO/c-Myc axis to promote tumor immune escape in ovarian cancer.
  11. Targeting PI3Kδ suppresses pancreatic cancer by dual disruption of fibrosis and immune evasion.
  12. Single-Cell Computational Frameworks for Quantifying BET Bromodomain Inhibitor Resistance and Screening Re-Sensitizer Drugs in Triple-Negative Breast Cancer.
  13. Lactylome Reprogramming Mediates Therapeutic Response and Adaptation to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.
  14. AKR1C3-PKM2-oxidative phosphorylation axis drives prostate cancer radioresistance via UBE2T upregulation.
  15. Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).
  16. H3K27ac-induced IFITM3 promotes progression of TNBC and resistance to anti-PD-1/PD-L1 therapy via the TNF-α/NF-κB/PD-L1 axis.
  1. FASEB J. 2026 Apr 15. 40(7): e71746
    Metabolic Response to CDK4/6 Inhibition in ER+ Breast Cancer Creates a Therapeutic Vulnerability in Drug-Tolerant Persister Cells.
    Huijuan Yang, Steven Tau, Andrew D McCray, Alyssa M Roberts, Jonathan D Marotti, Kristen Muller, Yuzhou Huang, Md Al Mamun, Kazuhiro Aoki, Eugene Demidenko, Todd W Miller.
      Although endocrine therapies prevent recurrence and progression of estrogen receptor alpha (ER)-positive breast cancer, approximately one-third of patients experience recurrent disease that is rarely cured in the advanced/metastatic setting. A subpopulation of endocrine-tolerant breast cancer cells persists as residual disease that confers risk for the eventual emergence of drug resistance. An analysis of persisters that continue to proliferate despite endocrine therapy revealed the activation of pathways related to metabolism and E2F transcription factor signaling. E2F signaling is driven by cyclin-dependent kinases 4 and 6 (CDK4/6), and CDK4/6 inhibitors (CDK4/6i) are used clinically to prevent and manage endocrine resistance. CDK4/6i slowed the cycling of endocrine-tolerant persisters. Analyzing metabolic alterations induced by CDK4/6i, we found that CDK4/6i-tolerant persisters had upregulation of mitochondrial content, mitochondrial membrane potential, respiration, and reactive oxygen species (ROS). Inhibition of mitochondrial complex I further increased ROS levels and enhanced growth inhibition in both endocrine-sensitive and -resistant cell lines and patient-derived xenografts. These findings collectively offer mitochondrial respiration as a therapeutic target in CDK4/6-tolerant persister breast cancer cells to help eradicate residual disease.
    Keywords:  CDK4/6; abemaciclib; breast cancer; drug resistance; drug‐tolerant persisters; metabolism; palbociclib
    DOI:  https://doi.org/10.1096/fj.202502515RR
  2. Cancer Med. 2026 Apr;15(4): e71780
    PSAT1 Promotes NSCLC Progression via the De Novo Serine Synthesis Pathway and Represents a Therapeutic Vulnerability.
    Xijia Zhou, Min Zhao, Yingshu Cao, Xiangyu Zhou, Ke Wang.
       BACKGROUND: Non-small cell lung cancer (NSCLC) is a malignant tumor characterized by high morbidity and mortality, as well as metabolic reprogramming. Enhanced serine synthesis plays a crucial role in the aberrant metabolism of NSCLC. Among the three key enzymes involved in serine synthesis, phosphoserine aminotransferase 1 (PSAT1) requires further investigation to elucidate its regulatory mechanisms in NSCLC.
    METHODS: In this study, we employed bioinformatics analysis, immunohistochemistry, CCK-8 assay, colony formation assay, flow cytometry assay, isotope tracing technique, WB analysis, and nude mouse xenograft models to validate the expression and function of PSAT1 in NSCLC.
    RESULTS: Our results demonstrated that PSAT1 was significantly upregulated in NSCLC cells and contributed to promoting cell proliferation, inhibiting apoptosis, and attenuating the efficacy of gefitinib treatment. Moreover, knockdown of PSAT1 led to inhibition of the de novo serine synthesis pathway (SSP), elevation of reactive oxygen species (ROS) levels, and activation of the mitochondrial apoptotic pathway. Notably, combined knockdown of PSAT1 with exogenous serine intake inhibition synergistically suppressed NSCLC progression.
    CONCLUSION: Collectively, our findings highlight that PSAT1 serves as a biomarker for metabolic reprogramming in NSCLC and exhibits a close association with disease development and treatment.
    Keywords:  PSAT1; ROS; apoptosis; de novo serine synthesis pathway; non‐small cell lung cancer
    DOI:  https://doi.org/10.1002/cam4.71780
  3. Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00263-9. [Epub ahead of print]45(4): 117185
    Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia.
    Léa Goupille, Alexandre Boudet, Laura Lauture, Ambrine Sahal, Guillaume Gautier-Renard, Emeline Chu-Van, Anvi Laetitia Nguyen, Céline Chollet, Coralie Alcazar, Isabelle Bernard, François Vergez, Véronique de Mas, Christian Récher, Tony Kaoma, Paolo Gallipoli, Vilma Dembitz, Irene Basili, Flavia Bernardi, Olivier Ayrault, Carine Joffre, Florence Castelli, Benoit Colsch, Nathalie Bourgès-Abella, Fanny Granat, Jean-Emmanuel Sarry.
      FMS-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) are associated with adverse prognosis. FLT3 inhibitors (FLT3i) improve therapeutic response; however, diverse resistance mechanisms, such as adaptations in lipid metabolism, have been identified. We hypothesized that a lipid-rich ketogenic diet (KD) might alter both host and tumoral lipid metabolism, enhancing responses to FLT3i. In FLT3-mutated AML mouse models, 3 weeks of lard- or plant-based KD improved the efficacy of FLT3i by 2-fold reduction of engraftment and tumor burden. KD increased ketone bodies and lipid accumulation in plasma, liver, and AML cells and also induced a polyunsaturated fatty acid:monounsaturated fatty acid (PUFA:MUFA) imbalance. KD impacted pentoses, hexoses, and amino acid metabolism, enhancing sugar phosphates and vitamins in the host. Mechanistically, KD rewired anabolism toward fatty acid oxidation and glycine-utilizing pathways, modulated the expression of FLT3 signaling pathways and lipid biosynthesis, and promoted tumor cell differentiation. In conclusion, this study shows that KD reduces FLT3i resistance, offering a promising therapeutic solution.
    Keywords:  CP: cancer; CP: metabolism; FLT3-ITD mutations; acute myeloid leukemia; ketogenic diet; metabolism; therapy resistance
    DOI:  https://doi.org/10.1016/j.celrep.2026.117185
  4. Sci Adv. 2026 Apr 03. 12(14): eaec8684
    Regulation of mitochondrial ROS by C15ORF48 in a basal cell subpopulation contributes to chemotherapy resistance in TNBC.
    Yan Jiang, Noor M Abdulkareem, Amanda L Rinkenbaugh, Yuan Qi, Steven W Wall, Xiaomei Zhang, Jiansu Shao, Sabrina Jeter-Jones, Shirong Cai, Faiza Baameur Hancock, Gloria V Echeverria, Jeffrey T Chang, Helen Piwnica-Worms.
      Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 (NDUFA4), while exhibiting reciprocal down-regulation of NDUFA4. Functionally, C15ORF48 knockdown sensitized breast cancer cells to AC, increasing reactive oxygen species (ROS) and apoptosis. Thus, the up-regulation of C15ORF48 blunts ROS accumulation and induces resistance to chemotherapy in the basal cell subpopulations. Our findings identify C15ORF48 as a potential therapeutic target for overcoming AC resistance in TNBC.
    DOI:  https://doi.org/10.1126/sciadv.aec8684
  5. Oncogene. 2026 Apr 01.
    LDHA-driven lactate metabolism promotes MDSC activation and immunosuppressive microenvironment in prostate cancer.
    Xiyi Wei, Xiao Li, Yitong Pan, Yuwei Zhang, Da Zhong, Weiyu Kong, Yue Wang, Zijie Yu, Wenchuan Shao, Yuxiang Dong, Silin Jiang, Zige Qiu, Yuwei Zhang, Xiang Li, Yize Li, Shouyong Gu, Chenxi Tian, Chao Qin, Qingyi Zhu, Ninghan Feng, Ninghong Song, Bing Yao, Zhou Yang.
      Immunotherapy has achieved limited efficacy in prostate cancer (PCa), largely due to its profoundly immunosuppressive tumor microenvironment (TME). However, the metabolic mechanisms underpinning this immune resistance remain poorly defined. Here, we identify lactate dehydrogenase A (LDHA)-driven lactate metabolism as a critical regulator of myeloid-derived suppressor cell (MDSC) activation in PCa. Integrated metabolomic, single-cell, and spatial transcriptomic analyses revealed that LDHA is highly expressed in PCa malignant epithelial cells and correlates with increased lactate production and immune exclusion. LDHA-high tumors exhibited enriched infiltration of polymorphonuclear MDSCs (PMN-MDSCs), which were spatially co-localized with LDHA-positive tumor regions. Mechanistically, lactate uptake through monocarboxylate transporter 1 (MCT1) enhanced PMN-MDSC differentiation and upregulated Arg1 and NOS2, reinforcing T cell suppression. Genetic ablation of LDHA in murine models markedly reduced PMN-MDSC infiltration, restored CD8+T cell activity, and inhibited tumor growth. Pharmacological inhibition of LDHA with FX-11 synergized with anti-PD-L1 therapy, producing durable tumor regression. Collectively, these findings define LDHA-driven lactate metabolism as a key metabolic checkpoint in PCa immune evasion and provide a rationale for combining LDHA inhibition with immune checkpoint blockade to overcome immunotherapy resistance.
    DOI:  https://doi.org/10.1038/s41388-026-03737-5
  6. Biomed Pharmacother. 2026 Apr 02. pii: S0753-3322(26)00306-9. [Epub ahead of print]198 119273
    Fatty Acid Synthase (FASN) as a targeted therapeutic in acquired 5-fluorouracil resistance in pancreatic cancer.
    Sara Noorani, Rían Ó Madáin, Jojanneke Stoof, Elodie Lepeltier, Esen Efeoglu, Michael Henry, Paula Meleady, Tia E Keyes, Naomi Walsh.
      Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies. The absence of early symptoms means that most patients are diagnosed at late stages with advanced disease. Despite progress in treatment, the overall prognosis remains poor mainly due to their inherent and/or acquired resistance to conventional therapies. The efficacy of new treatment strategies has been hampered by the lack of efficient preclinical models recapitulating the heterogeneity and complexity of this cancer resulting in the ineffective clinical translation of novel targeted therapeutic options. Acquired drug resistance to 5-fluorouracil (5-FU) (the backbone chemotherapeutic of treatment regimens for PDAC) in two patient-derived organoids (PDOs) were developed to investigate the mechanisms of chemotherapeutic resistance and identify novel targeted therapeutic strategies. Proteomic and pathway analyses identified Fatty Acid Synthase (FAS/FASN) as a key dysregulated protein with therapeutic vulnerabilities. Targeting FASN as a modulator of 5-FU resistance, via pharmacological inhibitor and phototoxic peptide conjugate, resensitised cells to 5-FU in acquired organoid models of resistance. PDOs are valuable tools for modelling drug resistance and offer opportunities to discover novel therapeutic approaches to circumvent the emergence of drug resistance.
    Keywords:  Acquired drug resistance; Patient-derived organoids; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.biopha.2026.119273
  7. Cell Rep Med. 2026 Mar 26. pii: S2666-3791(26)00121-7. [Epub ahead of print] 102704
    Targeting the noncanonical function of metabolic enzyme PHGDH in driving PD-L1 expression and cancer immune evasion.
    Juan Liu, Weiwei Wang, Yvonne Sun, Shan Huang, Arnav Borole, Haiyan Zheng, Wenwei Hu, Zhaohui Feng.
      Phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in serine synthesis, is frequently overexpressed in cancers and promotes cancer progression. Its oncogenic role has been largely attributed to its enzymatic activity. Here, we uncover a critical noncanonical function of PHGDH in cancer; PHGDH upregulates PD-L1 expression to promote cancer immune evasion independently of its enzymatic function. Mechanistically, PHGDH binds to the serine/threonine kinase RAF1 and disrupts its interaction with 14-3-3, thereby activating RAF1 and its downstream MEK/ERK signaling to induce PD-L1 expression. Elevated PHGDH levels correlate with increased PD-L1 expression in clinical tumor samples. In preclinical mouse models, tumors with high PHGDH expression exhibit increased sensitivity to PD-1/PD-L1 blockade. Combining PHGDH inhibitors with PD-1/PD-L1 blockade significantly improves antitumor effects compared to individual treatments. These results identify PHGDH as an important PD-L1 regulator, reveal a critical noncanonical mechanism underlying PHGDH's oncogenic function, and propose a potential therapeutic strategy for cancers with PHGDH overexpression.
    Keywords:  PD-L1; PHGDH; immune evasion; immune therapy; metabolism; noncanonical function; serine synthesis
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102704
  8. FASEB J. 2026 Apr 15. 40(7): e71726
    Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.
    Fan Wang, Ping Hu, Shengbo Han, Ya Zhang, Yang Li, Wenfeng Zhuo, Yong Zhao, Yan Huang, Guozheng Lv, Hongda Wang, Gang Zhao.
      Lactate has been considered as a tumor-promoting metabolite, however, its functional roles in pancreatic cancer (PC) have not yet been fully elucidated. Here, we explored the roles of lactate on the proliferation and invasion of PC cells under glucose deprivation. We found that lactate enhanced PC cells' proliferation and invasion under glucose deprivation, but not in normal conditions. The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset showed that monocarboxylic acid transporter 1 (MCT1), a lactate transporter, was overexpressed and correlated with poor prognosis in PC patients. Additionally, knockdown or inhibition of MCT1 distinctively attenuated lactate-induced proliferation and invasion of PC cells under glucose deprivation by suppressing their tricarboxylic acid (TCA) cycle. Importantly, the MCT1 inhibitor AZD3965 synergistically enhanced the anticancer effects of the glycolysis inhibitor 2-DG. Taken together, our results demonstrate that MCT1-mediated lactate influx sustains PC proliferation under glucose starvation, and combined inhibition of MCT1 and glycolysis could be leveraged for treatment of PC.
    Keywords:  MCT1; TCA; lactate; metastasis; proliferation
    DOI:  https://doi.org/10.1096/fj.202503162RR
  9. Nat Metab. 2026 Apr 01.
    NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions.
    Megan D Radyk, Barbara S Nelson, Mariana Tannus Ruckert, Christopher J Halbrook, Mengrou Shan, Jonathan M Alektiar, Brooke L Lavoie, Lucie Salvatore, Wei Yan, Matthew D Perricone, Kathryn Buscher, Alexander Wood, Hanna S Hong, Peter Sajjakulnukit, Li Zhang, Gabriel Corfas, Filip Bednar, Timothy L Frankel, Marina Pasca di Magliano, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis.
      Acinar-to-ductal metaplasia (ADM) is a reversible cell state that facilitates pancreas repair following injury. Oncogenic KRAS mutations can progress ADM to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). However, the metabolic alterations in these precancerous lesions are understudied. Here, we identify global changes in central carbon metabolism genes and metabolites during ADM formation. In particular, NRF2-target genes are significantly induced in ADM. Among these, we focus on genes encoding NADPH-producing enzymes glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which participate in the regulation of oxidative stress. In mouse models of pancreatic tumourigenesis, G6PD deficiency or Me1 loss increases reactive oxygen species and lipid peroxidation, which is accompanied by accelerated formation of ADM and PanIN lesions. Notably, Me1 loss, but not G6PD deficiency, promotes faster PDAC progression. We demonstrate that oxidative stress is required for ADM, as pharmacological antioxidant treatment attenuates ADM progression in vivo and ex vivo. Conversely, depleting the antioxidant glutathione promotes precancerous lesions in primary human acinar cells and in mice. Together, our findings shed light on metabolic reprogramming in the precancerous pancreas.
    DOI:  https://doi.org/10.1038/s42255-026-01496-x
  10. Cell Rep. 2026 Mar 31. pii: S2211-1247(26)00276-7. [Epub ahead of print]45(4): 117198
    PTEN loss drives B7H3 upregulation via the mTORC2/FOXO/c-Myc axis to promote tumor immune escape in ovarian cancer.
    Zhen Wang, Ning Jin, Xin Li, Xinyan Ma, Yuqing Feng, Kang Yin, Shican Duan, Wen Pan, Jin-Kai Jiang, Le-Lin Lei, Yi-Yu Qian, Xulei Zheng, Qing-Lei Gao, Dan Liu, Yu Xia.
      Immune checkpoint blockade (ICB) therapy has shown limited efficacy in ovarian cancer (OC). PTEN loss is a common driver in OC, yet its impact on ICB efficacy remains poorly understood. Utilizing the single-cell RNA sequencing data and performing multiplex immunohistochemical staining on treatment-naive OC clinical specimens, we showed that PTEN reduction resulted in an immunosuppressive tumor microenvironment associated with upregulated B7H3. Mechanistically, PTEN depletion activates mTORC2, which phosphorylates FOXO1/3, thereby inhibiting their transcriptional activity and reducing MXI1 expression. This, in turn, diminishes the inhibitory effect on c-Myc, leading to enhanced c-Myc transcriptional activity and subsequent upregulation of B7H3. Notably, in mouse models, anti-B7H3 therapy exhibits heightened effectiveness in OC with PTEN loss. This enhanced response can be abrogated by removing CD8+ T cells. Our findings elucidate an immune evasion mechanism in PTEN-loss OC and suggest B7H3 blockade as a potent therapeutic strategy specifically for these tumors.
    Keywords:  B7H3; CP: cancer; PTEN; c-Myc; immune checkpoint; mTORC2; ovarian cancer; precision immunotherapy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117198
  11. Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00266-4. [Epub ahead of print]45(4): 117188
    Targeting PI3Kδ suppresses pancreatic cancer by dual disruption of fibrosis and immune evasion.
    Maciej Garczyk, Gonçalo Outeiro-Pinho, Muthita Pitaktrairat, Bárbara Sofia Soares Da Silva, Giusy Di Conza, Karolina Niewola-Staszkowska, Marcel A Deken, Zoë Johnson, Asmita Thapa, Flavia Fico, Matteo Rossi Sebastiano, Inés Reynoso-Moreno, Daniele Pellegata, Giorgio Ramadori, Beat Gloor, Martin Wartenberg, Jürg Gertsch, Georgia Konstantinidou.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal fibrosis that promotes immune exclusion and treatment resistance, yet the upstream drivers of this pro-fibrotic cascade remain poorly defined. Here, we identify phosphoinositide 3-kinase δ (PI3Kδ) as a previously unrecognized driver of fibrosis in PDAC. Pharmacological inhibition of PI3Kδ reduces collagen deposition while enhancing the infiltration of activated CD8+ T cells, thereby reprogramming the tumor microenvironment toward an antitumor state. Mechanistically, we reveal that PI3Kδ regulates the biosynthesis of lysophosphatidic acid (LPA), a key lipid mediator of stromal remodeling, by controlling phosphatidylcholine-derived precursors in both cancer cells and stromal fibroblasts. By regulating both LPA-driven stromal remodeling and immune suppression, PI3Kδ emerges as a central regulator of the PDAC tumor microenvironment. Co-inhibition of autotaxin, an enzyme contributing to LPA production, and PI3Kδ further amplifies stromal disruption and improves chemo-immunotherapy efficacy in preclinical PDAC models. These findings position PI3Kδ as a central therapeutic target in PDAC, offering a dual-action strategy to simultaneously dismantle stromal fibrosis and immune suppression.
    Keywords:  CP: cancer; CP: immunology; immunosuppression; pancreatic ductal adenocarcinoma; targeted therapies; tumor lipid metabolic regulation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.117188
  12. Adv Sci (Weinh). 2026 Apr 03. e13246
    Single-Cell Computational Frameworks for Quantifying BET Bromodomain Inhibitor Resistance and Screening Re-Sensitizer Drugs in Triple-Negative Breast Cancer.
    Haizhou Liu, Mengqin Yuan, Yini Shang, Jiahao Chen, Fei Hou, Lihong Wang, Wei Jiang.
      Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by rapid proliferation and a great propensity for metastasis. Therapeutic options for TNBC remain limited due to the absence of targetable hormone receptors. While BET bromodomain inhibitors (BBDIs) exhibit promising anticancer potential, the emergence of drug resistance presents a major challenge. Here, through leveraging single-cell RNA sequencing (scRNA-seq) data across continuous states of BBDI treatment in TNBC, this study conducts an extensive investigation into BBDI resistance, and develops two computational frameworks, FR20 and D-FR20, to quantify BBDI resistance at single-cell resolution and to screen potential BBDI re-sensitizer drugs, respectively. The accuracy and scalability of FR20 are confirmed through rigorous evaluation in nine independent datasets. In addition, cellular dynamic changes and ferroptosis inhibition are revealed in the evolution of BBDI resistance. Experimental validation demonstrates that GPX4 overexpression significantly reduces drug sensitivity in TNBC cells. Furthermore, in vitro and in vivo experiments validate the ability of the small molecule filgotinib, identified by D-FR20, to re-sensitize BBDI and effectively eliminate resistant TNBC cells. Collectively, this study provides two computational frameworks for predicting BBDI resistance and candidate re-sensitizer, as well as demonstrates the roles of ferroptosis in BBDI resistance, offering a promising avenue for TNBC treatment.
    Keywords:  BET bromodomain inhibitor; drug resistance; ferroptosis; scRNA‐seq; triple‐negative breast cancer
    DOI:  https://doi.org/10.1002/advs.202513246
  13. Mol Cell Proteomics. 2026 Mar 31. pii: S1535-9476(26)00057-5. [Epub ahead of print] 101561
    Lactylome Reprogramming Mediates Therapeutic Response and Adaptation to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.
    Panpan Peng, Xinyi Cen, Tianxiao Wang, Shuang Wei, Xinbo Wang, Xuelian Ren, Cong Yan, Yongjun Zhu, Qian Niu, Lu Chen, Qi Mei, Xiansheng Liu, Qunyi Li, He Huang.
      Esophageal squamous cell carcinoma (ESCC) exhibits high prevalence in China and poor prognosis despite neoadjuvant chemotherapy (NACT), with significant chemoresistance development. Tumor-associated metabolic reprogramming and NACT-induced cellular stress promote lactate accumulation, which serves as a precursor for lysine lactylation (Kla), a post-translational modification (PTM) potentially regulating cancer progression. We hypothesized that systematic characterization of the lactylome in response to NACT could reveal critical molecular mechanisms underlying treatment and identify new therapeutic vulnerabilities in ESCC. Herein, through comprehensive proteomic and lactylome profiling of tumor and adjacent normal tissues from 31 ESCC patients (with or without NACT treatment), we identified 8281 proteins and 1836 Kla sites across 62 samples. NACT induced substantial lactylome alterations with 307 differentially expressed Kla sites predominantly in non-histone proteins involved in DNA damage response and metabolic pathways. Our data revealed that while NACT-induced suppression of energy metabolism, coupled with upregulated HRD1 complex expression, may exert potential pro-apoptotic effects, the activation of ribosome biogenesis and increased nucleoprotein lactylation triggered tumor-protective mechanisms. Mechanistically, we demonstrated that DNA damage and elevated lactate levels induced PARP1 K654 lactylation, enhancing its enzymatic activity and augmenting poly(ADP-ribosyl)ation of downstream targets, potentially playing a pivotal role in chemotherapy resistance-associated pathways. This comprehensive tissue-level landscape of Kla dynamics in ESCC response to chemotherapy establishes Kla as a critical regulatory mechanism in treatment response, potentially offering novel therapeutic targets and predictive biomarkers for personalized treatment strategies.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101561
  14. Cell Death Dis. 2026 Mar 30.
    AKR1C3-PKM2-oxidative phosphorylation axis drives prostate cancer radioresistance via UBE2T upregulation.
    Jinyu Zhang, Jiongzheng Li, Yufei Yan, Binghuan Wang, Ruojia Wang, Xiaoli Cui, Yang Zhan, Zuowen Liang, Jing Li.
      Radioresistance is one of the primary causes of prostate cancer treatment failure and post-radiotherapy progression. However, there is currently a lack of effective targets to increase radiotherapy sensitivity and inhibit malignant progression. We identified AKR1C3 as a potential key target associated with radioresistance and malignant progression through integrated bioinformatic analysis of RNA sequencing (RNA-seq) data from prostate cancer clinical samples in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The promotion of radioresistance by AKR1C3 in both AR-positive and AR-negative prostate cancer cells was further validated through in vivo and in vitro experiments. Mechanistic studies revealed that AKR1C3 can bind to PKM2 and accelerate its degradation, thereby inhibiting glycolytic flux and enhancing oxidative phosphorylation (OXPHOS). Increased OXPHOS boosts ROS production, which further promotes NRF2 nuclear translocation, activating the transcription of DNA repair protein UBE2T. This enhanced DNA damage repair ability enables prostate cancer cells with high AKR1C3 expression to exhibit greater resistance to radiotherapy. In summary, this study reveals the molecular mechanism by which AKR1C3 is involved in metabolic reprogramming to promote radioresistance in prostate cancer through PKM2/UBE2T. These findings indicate that targeting AKR1C3 has potential for overcoming radioresistance, providing novel insight into the clinical treatment of prostate cancer.
    DOI:  https://doi.org/10.1038/s41419-026-08666-5
  15. Cell Commun Signal. 2026 Mar 28.
    Metabolic reprogramming and cisplatin resistance: the emerging role of Pyruvate Dehydrogenase Kinases (PDKs).
    Aishath Shaheeda, Shama Prasada Kabekkodu.
      
    Keywords:  Cisplatin resistance; Glycolysis; Metabolic reprogramming; Pyruvate dehydrogenase kinase; Redox homeostasis; Warburg effect
    DOI:  https://doi.org/10.1186/s12964-026-02845-9
  16. Biochim Biophys Acta Mol Basis Dis. 2026 Apr 01. pii: S0925-4439(26)00101-8. [Epub ahead of print] 168238
    H3K27ac-induced IFITM3 promotes progression of TNBC and resistance to anti-PD-1/PD-L1 therapy via the TNF-α/NF-κB/PD-L1 axis.
    Guangyan Li, Baiyang Fu, Xi Wang, Haiyun Lin, Xi Chen, Jianguo Zhang.
      Triple-negative breast cancer (TNBC) is highly malignant with limited effective targeted therapies, leading to poor patient outcomes. Although immune checkpoint inhibitors (ICIs) have shown promise in cancer treatment, most patients with TNBC exhibit primary or secondary resistance to ICIs, restricting their clinical use. Interferon-induced transmembrane protein 3 (IFITM3), an interferon-induced protein, is highly overexpressed in various tumors and is associated with immune suppression; however, its role in TNBC progression and immune escape remains unclear. In this study, we investigated IFITM3 expression and its prognostic relevance in TNBC via bioinformatics and clinical validation and explored its functional effects through in vitro and in vivo experiments. IFITM3 was highly expressed in TNBC and correlated with poor prognosis. Its knockdown inhibited proliferation, migration, and invasion, promoted apoptosis, and reduced tumor xenograft growth. Enriched histone H3 lysine 27 acetylation (H3K27ac) in the promoter region led to enhanced IFITM3 transcription. IFITM3 activates the tumor necrosis factor (TNF)-α/nuclear factor kappa B (NF-κB) pathway, leading to upregulated programmed death-ligand 1 (PD-L1) expression, which promotes tumor progression and immune evasion. Blocking the TNF-α/NF-κB pathway reverses the pro-cancer effects of IFITM3. IFITM3 overexpression induced resistance to anti-PD-1 therapy, whereas its knockdown enhanced treatment sensitivity, decreased tumor volume, prolonged survival, increased CD8+ T-cell infiltration, and enhanced tumor apoptosis. In summary, this study revealed that H3K27ac drives IFITM3 transcription in TNBC, activating the TNF-α/NF-κB/PD-L1 axis to promote tumor progression and immunotherapy resistance. Targeting IFITM3 may overcome anti-PD-1 resistance and improve TNBC treatment outcomes.
    Keywords:  H3K27ac; PD-1 resistance; TNBC; TNF-α/NF-κB signaling pathway; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168238
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