bims-meract 2026-01-11 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–01–11
fourteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

PRMT5 upregulates KCNMB4 expression via histone methylation to promote paclitaxel resistance in advanced nasopharyngeal carcinoma.
The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in MM by modulating mitochondrial metabolism.
Targeting PPP1R15B and ATF4 Axis in Hepatocellular Carcinoma: A Novel Strategy for Overcoming Lenvatinib-Tolerant Persister Cells Through GPX4-Mediated Ferroptosis Induction.
Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
Inhibition of GPX4 induces the death of p53-mutant triple-negative breast cancer cells.
Arachidonic acid-functionalized micelle induces ferroptosis of tumor cells to overcome chemotherapy resistance for breast cancer therapy.
Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic perturbations in bladder cancer.
PROTAC‑Mediated HMGCR Depletion Reprograms Lipid Metabolism in Breast Cancer to Potentiate Photoimmunotherapy via Ferroptosis.
ATGL suppresses ferroptosis in acute myeloid leukemia cells by modulating the CEBPα/SCD1 axis and induces gilteritinib resistance.
HMGB1 Assists in Overcoming Cisplatin Resistance in Chemoresistant Human Ovarian Cancer Cells.
Nutrient requirements of organ-specific metastasis in breast cancer.
SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.
Metabolic alterations driven by PFKFB3 upregulation confer resistance to trastuzumab in HER2-positive breast cancer.
Elucidating cooperative genetic events in DCIS progression in mutant p53-driven breast cancer.

Cell Death Dis. 2026 Jan 09. 17(1): 19

PRMT5 upregulates KCNMB4 expression via histone methylation to promote paclitaxel resistance in advanced nasopharyngeal carcinoma.

Lizhen Liu, Sailan Liu, Yali Wang, Peili Wang, Guixiang Zhong, Jing Han Hong, Rong Xiao, Yaoyu Guo, Fang Zhu, Jing Hao, JianFeng Chen, Hai-Qiang Mai, Jing Tan.

Concurrent chemotherapy is the standard treatment strategy for advanced-stage nasopharyngeal carcinoma (NPC). However, chemoresistance inevitable develops and the underlying mechanism remains poorly understood. In this study, we identify the arginine methyltransferase PRMT5 as a key gene associated with chemoresistance to paclitaxel in NPC. We demonstrate that PRMT5 facilitated paclitaxel resistance by inducing KCNMB4 expression in nasopharyngeal carcinoma cells. Mechanistically, PRMT5 is recruited to the promoter region of KCNMB4, where it catalyzes H3R2me2s and enhances KCNMB4 expression. Furthermore, elevated levels of PRMT5 or KCNMB4 correlated with poorer survival and higher recurrence rates in NPC patients. Notably, genetic or pharmacological inhibition of PRMT5 significantly sensitized NPC cells to paclitaxel, both in vitro and in vivo. Collectively, these results suggest that the PRMT5-KCNMB4 axis plays a crucial role in mediating chemoresistance in NPC and targeting this axis may provide a promising therapeutic strategy for late-stage NPC patients.

DOI: https://doi.org/10.1038/s41419-025-08190-y
Cancer Lett. 2026 Jan 07. pii: S0304-3835(26)00008-X. [Epub ahead of print] 218245

The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in MM by modulating mitochondrial metabolism.

Chenggong Tu, Arne Van der Vreken, Sylvia Faict, Gamze Ates, Ann Massie, Kim De Veirman, Elke De Bruyne, Karin Vanderkerken, Eline Menu.

  Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells residing in the bone marrow. Despite advancements in treatment, including proteasome inhibitors (PIs) such as bortezomib (Bz), drug resistance remains a major challenge. Metabolic reprogramming supports MM survival and drug resistance, with mitochondria emerging as promising therapeutic targets through their control of OXPHOS and mitochondrial reactive oxygen species (Mito-ROS). Using metabolic flux analyses, flow cytometry, and Western blot analysis, we identified pyruvate as a central metabolic intermediate, which not only enhances mitochondrial respiration and Mito-ROS production, but also the Integrated Stress Response (ISR) pathway. Conversely, metformin, an inhibitor of OXPHOS, was still able to activate the ISR pathway, but rather reduced Bz-induced cytotoxicity by decreasing both protein synthesis, and ROS production. Results were confirmed on primary murine and patient samples. Moreover, analysis of the CoMMpass study revealed that patients with prolonged progression-free survival under PI treatment showed enrichment in OXPHOS-related gene, highlighting the importance of mitochondrial metabolism in regulating MM responses to Bz. These data suggest that targeting pyruvate metabolism to increase ROS production could offer a strategy to enhance Bz activity in MM.

Keywords:  ISR; bortezomib; metformin; multiple myeloma; pyruvate

DOI:  https://doi.org/10.1016/j.canlet.2026.218245
Eur J Pharm Sci. 2026 Jan 07. pii: S0928-0987(26)00008-4. [Epub ahead of print] 107434

Targeting PPP1R15B and ATF4 Axis in Hepatocellular Carcinoma: A Novel Strategy for Overcoming Lenvatinib-Tolerant Persister Cells Through GPX4-Mediated Ferroptosis Induction.

Ming-Yao Chen, Shiue-Wei Lai, Yi-Chiao Cheng, Vijesh Kumar Yadav, Iat-Hang Fong, Kuang-Tai Kuo, Kuen-Haur Lee, Yih-Giun Cherng.

   BACKGROUND: Lenvatinib is a first-line therapy for advanced hepatocellular carcinoma (HCC), yet the emergence of lenvatinib-tolerant persister cells (LTPCs) contributes to therapeutic failure and tumor relapse. The molecular programs that sustain this tolerant state remain insufficiently defined. Here, we investigated the role of the PPP1R15B-ATF4 stress-response axis in mediating lenvatinib tolerance and ferroptosis resistance.
METHODS: LTPCs were generated from multiple HCC cell lines through continuous lenvatinib exposure and confirmed by phenotypic and molecular profiling. Transcriptomic analysis (RNA-seq) was performed to identify pathways enriched in LTPCs. Functional relevance of the PPP1R15B-ATF4-GPX4 axis was evaluated using genetic perturbation (siRNA/CRISPR) and pharmacologic inhibition. Redox homeostasis, lipid peroxidation, and ferroptosis susceptibility were assessed through biochemical and imaging assays. An LTPC xenograft mouse model was used to evaluate in vivo therapeutic efficacy.
RESULTS: RNA-seq revealed that LTPCs exhibit robust activation of the PPP1R15B-ATF4-GPX4 signaling axis, accompanied by enhanced redox buffering and suppression of ferroptotic vulnerability. Mechanistic studies demonstrated that PPP1R15B stabilizes ATF4, which in turn transcriptionally upregulates GPX4, thereby sustaining the drug-tolerant persister phenotype. Genetic or pharmacological inhibition of PPP1R15B disrupted ATF4-GPX4 signaling, impaired redox homeostasis, increased lipid peroxidation, and effectively re-sensitised LTPCs to ferroptosis and lenvatinib. In vivo, PPP1R15B inhibition significantly reduced LTPC survival and restored lenvatinib responsiveness in xenograft models.
CONCLUSION: The PPP1R15B-ATF4-GPX4 axis is a key determinant of lenvatinib tolerance in HCC by orchestrating redox adaptation and ferroptosis resistance. Targeting PPP1R15B represents a promising therapeutic strategy to eliminate lenvatinib-tolerant persister cells and overcome acquired resistance in HCC.

Keywords:  ATF4; Drug-tolerant persister cells; Ferroptosis; GPX4; Hepatocellular carcinoma; Lenvatinib; PPP1R15B

DOI:  https://doi.org/10.1016/j.ejps.2026.107434
Mol Metab. 2026 Jan 06. pii: S2212-8778(25)00223-6. [Epub ahead of print] 102316

Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.

Maxime Labroy, Marc-Oliver Paré, Line Berthiaume, Mélissa Thomas, Cynthia Jobin, Alain Veilleux, Martin Pelletier, Frédéric Pouliot, Jean-Yves Masson, Étienne Audet-Walsh.

  Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.

Keywords:  BAY-2402234; DHODH; NEPC; androgen receptor; aspartate; cancer metabolism; castration-resistant prostate cancer; glucose; glutamine; mitochondria; neuroendocrine differentiation; neuroendocrine prostate cancer; nucleotide synthesis; prostate cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102316
Breast Cancer Res Treat. 2026 Jan 06. 215(2): 49

Inhibition of GPX4 induces the death of p53-mutant triple-negative breast cancer cells.

William M Tahaney, Amanda Lanier, Jing Qian, Cassandra L Moyer, Nghi Nguyen, Yanxia Ma, Jamal Hill, Reid T Powell, Clifford C Stephan, Peter J A Davies, Abhijit Mazumdar, Powel H Brown.

   BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high rates of tumor protein 53 (TP53) mutation and with limited targeted therapies. Despite being clinically advantageous, direct targeting of mutant TP53 has been challenging. Therefore, we hypothesized that p53-mutant TNBC cells rely upon other potentially targetable survival pathways.
METHODS: In vitro and in silico screens were used to identify drugs that induced preferential death in TP53-mutant cells. The effect of the ferroptosis inducer ML-162 was tested both in vitro and in vivo and the mechanism of cell death following ML-162 treatment or GPX4 knockout was determined.
RESULTS: High-throughput drug screening demonstrated that TP53-mutant TNBCs are highly sensitive to peroxidase, cell cycle, cell division, and proteasome inhibitors. We further characterized the effect of the ferroptosis inducer ML-162 and demonstrated that ML-162 induces preferential ferroptosis in TP53-mutant TNBC cells. Treatment of TP53-mutant xenografts with ML-162 suppressed tumor growth and increased lipid peroxidation in vivo. Testing ferroptosis inducers demonstrated TP53-missense mutant, and not TP53-null or wild-type cells, were more sensitive to ferroptosis, and expression of mutant TP53 genes in p53-null cells sensitized cells to ML-162 treatment.
CONCLUSIONS: This study demonstrates that TP53-mutant TNBC cells have unique survival pathways that can be effectively targeted. Our results illustrate the intrinsic vulnerability of TP53-mutant TNBCs to ferroptosis and highlight GPX4 as a potential target for the precision treatment of TP53-mutant TNBC.

Keywords:   p53 ; Ferroptosis; GPX4; Gain-of-function; TNBC; TP53

DOI:  https://doi.org/10.1007/s10549-025-07865-6
Int J Pharm. 2026 Jan 06. pii: S0378-5173(26)00014-1. [Epub ahead of print]690 126566

Arachidonic acid-functionalized micelle induces ferroptosis of tumor cells to overcome chemotherapy resistance for breast cancer therapy.

Shuang Chen, Xuan He, Yunxia Ye, Shiyu Zhu, Zhipeng Tian, Mingrui Yang, Shuochen Pang, Man Li, Rong Guo, Qin He.

  Chemotherapy plays an irreplaceable role in the clinical treatment of malignant tumors, yet drug resistance remains a major cause of suboptimal therapeutic outcomes. Ferroptosis, a regulated cell death modality, offers a promising therapeutic strategy, as the chemotherapy-resistant tumor cells exhibit heightened sensitivity to this process. Combining chemotherapeutics with ferroptosis-inducing agents thus represents a viable approach to overcome chemotherapy resistance. The accumulation of polyunsaturated fatty acids (PUFAs) is an important factor contributing to the increase of lipid peroxides and triggering ferroptosis, and arachidonic acid (AA) is a typical type of PUFAs. Based on that, we designed an amphiphilic polymer dextran-AA (Dex-AA), and constructed an AA-functionalized micelle DA through its self-assembly, with the chemotherapeutic drug doxorubicin (DOX) encapsulated within the cores. The obtained micelle DA/DOX induced ferroptosis by promoting lipid peroxidation, which significantly enhanced the cytotoxicity of DOX against DOX-resistant tumor cells. Meanwhile, DA/DOX synergistically maintained high intracellular drug levels via an "open-source throttling" strategy by both promoting uptake via the enhanced membrane fluidity and inhibiting ATP-dependent efflux through ROS-induced mitochondrial damage/ATP depletion. In vitro studies confirmed the excellent efficacy of DA/DOX in both 4T1 and MCF-7/ADR cells. Furthermore, in the breast cancer mouse model, DA/DOX exhibited superior antitumor effects compared to the long-circulating DOX liposomes (Lip/DOX). This study presents a novel strategy based on ferroptosis to overcome chemotherapy resistance of breast cancer, which is of great significance.

Keywords:  Breast cancer; Drug resistance; Ferroptosis; Micelles; Polyunsaturated fatty acid (PUFA)

DOI:  https://doi.org/10.1016/j.ijpharm.2026.126566
Nat Commun. 2026 Jan 07.

Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic perturbations in bladder cancer.

Pratishtha Singh, Ranit D'Rozario, Bidisha Chakraborty, Swadhin Meher, Deblina Raychaudhuri, Aminah J Tannir, Yang Li, Anurag Majumdar, Jessalyn Hawkins, Yun Xiong, Philip Lorenzi, Padmanee Sharma, Kadir Akdemir, Patrick Pilie, Abhinav K Jain, Byron Hing Lung Lee, Sangeeta Goswami.

Mutations in epigenetic regulators are common in bladder cancer, yet their impact on therapeutic responses remains unclear. Here, we identify that loss-of-function mutations in KDM6A, a histone demethylase altered in about 26% of advanced bladder cancers, are associated with poor survival after cisplatin chemotherapy, whereas they correlate with improved outcomes with anti-PD-1 therapy. Using CRISPR-Cas9-engineered murine and human bladder cancer models, we show that KDM6A deficiency increases formation of extrachromosomal circular DNA carrying chemoresistance loci, promoting cisplatin resistance. In parallel, KDM6A loss impairs DNA repair and rewires tumor metabolism, reducing glycolysis and lactate output. This metabolic shift diminishes histone lactylation in regulatory T cells, suppressing immunoregulatory genes and limiting expansion of PD-1hi regulatory T cells. Collectively, our findings establish KDM6A mutation as a key regulator of therapeutic responses, providing a foundation for its use in guiding precision therapy in advanced bladder cancer.

DOI: https://doi.org/10.1038/s41467-025-68132-2
Adv Sci (Weinh). 2026 Jan 04. e21525

PROTAC‑Mediated HMGCR Depletion Reprograms Lipid Metabolism in Breast Cancer to Potentiate Photoimmunotherapy via Ferroptosis.

Tong Su, Guang Li, Yudong Guan, Qi Tian, Youzhi Qi, Yanqiu Zhang, Wenqian Wei, Xinxin Duan, Jiaxin Rui, Hongyan Zhu, Zengping Lin, Changchuan Xie, Zheni Xu, Yaying Wu, Xin Peng, Zhenjie Wang, Kun Chen, Xiaoyan Xin, Bing Zhang.

  Aberrant lipid metabolism characterizes the progression of breast cancer. Statins, the canonical agents for modulating this pathway, have been associated with improved overall survival in patients with triple-negative breast cancer (TNBC). However, their clinical benefit remains limited because the reversible inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) elicits a rebound in the mevalonate pathway and enables evasion of ferroptosis. Therefore, we developed a 170 nm self-assembled nanomedicine (PRO-P) that integrates an HMGCR-targeting PROTAC (PRO) with a disulfide-linked Pyropheophorbide-a (Ppa) photosensitizer, enabling laser-gated protein HMGCR degradation and photodynamic stress within one formulation. Under laser irradiation, PRO-P catalytically depletes HMGCR while generating reactive oxygen species (ROS), collapsing the mevalonate/CoQ10-GPX4 axis and redirecting lipids into ferroptosis. In 4T1 cells, PRO-P enhanced cellular uptake by 1.34-fold and elevated ROS by 9.5-fold. Following intravenous administration in TNBC xenografts, PRO-P achieved 92.5% tumor regression, eradicated pulmonary metastases, and elicited no systemic toxicity after single laser exposure. Immune profiling revealed remodeling of the microenvironment, with 2.6-fold more CD8⁺ Granzyme-B⁺ T cells, 4.3-fold more mature dendritic cells, and fewer Tregs, thereby establishing durable memory. PRO-P exploits multi-omics-guided HMGCR targeting to convert lipid addiction into a redox-immunologic vulnerability, yielding a low-toxicity therapy for TNBC and other lipid-driven cancers.

Keywords:  PROTAC (proteolysis‐targeting chimera); breast cancer; ferroptosis; lipid metabolism; mevalonate pathway; photoimmunotherapy

DOI:  https://doi.org/10.1002/advs.202521525
Cell Death Dis. 2026 Jan 09.

ATGL suppresses ferroptosis in acute myeloid leukemia cells by modulating the CEBPα/SCD1 axis and induces gilteritinib resistance.

Shiyi Yuan, Ying Zhou, Wenrui Xiao, Ning Liu, Ping Zhang, Ying Zhang, Jianchuan Deng, Liang Fang, Xi Zhang, Shifeng Lou.

Metabolic reprogramming disrupts energy homeostasis and promotes tumor cell proliferation. In the present study, high expression of adipose triglyceride lipase (ATGL) in patients with acute myeloid leukemia (AML) predicted a poor clinical prognosis. Furthermore, the aberrant upregulation of ATGL was confirmed to promote the malignant progression of AML through gene ablation, overexpression, and pharmacological inhibition of ATGL, particularly in FLT3-ITD-mutated AML. RNA sequencing, lipid peroxidation, cellular iron, and ROS assays were performed to confirm the association of ATGL with ferroptosis. Mechanistically, ATGL is positively correlated with stearoyl-CoA decarboxylase 1 (SCD1) and promotes the malignant progression of AML by inhibiting ferroptosis through the CEBPα/SCD1 axis. We established gilteritinib-resistant MOLM-13 and MV4-11 cell lines and collected cells from patients with FLT3-ITD mutations to confirm that ATGL inhibitors increased the efficacy of gilteritinib. Consequently, we constructed an AML xenograft model using cells derived from patients with FLT3-ITD-mutated AML to confirm the efficacy of combining ATGL inhibitors with gilteritinib in vivo. This study provides novel therapeutic targets and monitoring indicators for AML, along with new treatment strategies for patients with FLT3-ITD-mutated AML and those with relapsed/refractory FLT3-ITD-mutated AML.

DOI: https://doi.org/10.1038/s41419-025-08388-0
Mol Carcinog. 2026 Jan 09.

HMGB1 Assists in Overcoming Cisplatin Resistance in Chemoresistant Human Ovarian Cancer Cells.

Van Huynh, Guliang Wang, Anirban Mukherjee, Karen M Vasquez.

Cisplatin is one of the most effective chemotherapeutic agents used in the treatment of ovarian cancer. However, the frequent development of cisplatin resistance remains a significant limitation, leading to therapeutic failure and poor patient outcomes. Cisplatin cytotoxicity is attributed to the generation of toxic DNA lesions, which can be recognized and processed by a variety of proteins, including the high mobility group box 1 (HMGB1) protein. HMGB1 is a multifunctional protein, which is involved in chromatin remodeling and multiple DNA damage repair pathways. In this study, we investigated the role of HMGB1 in modulating cisplatin sensitivity in human ovarian cancer cells. Using cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines, we employed siRNA-mediated HMGB1 knockdown to assess its impact on the cellular responses to cisplatin treatment. In clonogenic survival assays, HMGB1 depletion resulted in a significant reduction in colony formation in cisplatin-resistant cells upon cisplatin exposure, compared with nontargeting siRNA treated cells. Additionally, HMGB1 inhibition significantly enhanced cisplatin-induced apoptosis in the cisplatin-resistant cells. Mechanistically, HMGB1-depleted cells exhibited altered DNA damage responses via modulation of ATM/CHK2 and ATR/CHK1 activity following cisplatin treatment. Notably, DNA immunoblot and modified alkaline comet assay results demonstrated that HMGB1 depletion stimulated cisplatin-DNA adduct formation and impaired the removal of cisplatin-DNA adducts, particularly in the cisplatin-resistant cells. Collectively, these findings uncover novel functions of HMGB1 in mediating cisplatin sensitivity, emphasizing its potential as a therapeutic target to overcome cisplatin resistance in ovarian cancer.

DOI: https://doi.org/10.1002/mc.70074
Nature. 2026 Jan 07.

Nutrient requirements of organ-specific metastasis in breast cancer.

Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Diya L Ramesh, Sophie E Honeder, Ashwin S Kumar, Michelle Wu, Jacob A Hansen, Anna Shevzov-Zebrun, Edrees H Rashan, Kian M Eghbalian, Sharanya Sivanand, Anna M Barbeau, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E Trojan, Millenia Waite, Tenzin Kunchok, Mayu A Nakano, Florian Gourgue, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.

Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.

DOI: https://doi.org/10.1038/s41586-025-09898-9
Nat Cell Biol. 2026 Jan 07.

SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.

Lei Wang, Han Chu, Degao Chen, Yuxuan Wei, Jia Jia, Liqi Li, Linfeng He, Lina Peng, Fangfang Liu, Shanshan Huang, Zheng Jin, Dong Zhou, WenFeng Fang, Tao Jiang, Shouxia Xu, Xiaofang Ding, Haoyang Cai, Xindong Liu, Qingzhu Jia, Bo Zhu, Qian Chu.

Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC.

DOI: https://doi.org/10.1038/s41556-025-01840-5
Biomed Pharmacother. 2026 Jan 06. pii: S0753-3322(25)01092-3. [Epub ahead of print]194 118898

Metabolic alterations driven by PFKFB3 upregulation confer resistance to trastuzumab in HER2-positive breast cancer.

Roos Vincken, Samuel T Pasco, Veronica Steri, Laura Bozal-Basterra, Wilfred F J van IJcken, Arkaitz Carracedo, Danny Huylebroeck, Mark M Moasser, Ana Ruiz-Sáenz.

   AIMS: Resistance to anti-HER2 therapies, particularly trastuzumab, remains a major obstacle in the treatment of HER2-positive (HER2 +) breast cancer. This study aims to uncover novel mechanisms driving trastuzumab resistance with a focus on the immune component, key mediator of trastuzumab efficacy.
METHODS: We developed an isogenic cell line-derived xenograft model to perform transcriptome-wide analyses of trastuzumab-sensitive and -resistant tumors. To validate key findings, we employed a 3D cancer-immune co-culture system capable of quantifying antibody-dependent cellular cytotoxicity (ADCC).
RESULTS: Transcriptomic profiling revealed how trastuzumab treatment shifts tumor transcriptomes, including changes that remodel the metabolic landscape and distinct gene signatures associated with resistance, notably the upregulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Functional studies demonstrated that PFKFB3 promotes trastuzumab resistance by inducing metabolic rewiring and reducing ADCC. Silencing PFKFB3 restored immune-mediated cytotoxicity. Clinical dataset analyses confirmed that elevated PFKFB3 expression correlates with reduced overall and progression-free survival, and with incomplete pathological response to trastuzumab.
CONCLUSIONS: PFKFB3 upregulation drives metabolic adaptations that confer resistance to trastuzumab in HER2 + breast cancer. These findings highlight PFKFB3 as a promising therapeutic target to overcome resistance and improve patient outcomes.

Keywords:  ADCC; HER2-targeting therapy; breast cancer; trastuzumab; treatment resistance

DOI:  https://doi.org/10.1016/j.biopha.2025.118898
Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2526544123

Elucidating cooperative genetic events in DCIS progression in mutant p53-driven breast cancer.

Rhiannon L Morrissey, Joy M McDaniel, Gilda P Chau, Xiaoping Su, Mitheera V, Vidhi Chandra, Beverly R E A Dixon, Adel K El-Naggar, Alastair M Thompson, Guillermina Lozano.

  Ductal carcinoma in situ (DCIS) is a precursor mammary lesion characterized by abnormal epithelial cells in mammary ducts that remain confined to the luminal space. Not all DCIS becomes invasive, and no strategy currently exists in patients to stratify indolent DCIS from DCIS at risk of progression. Several studies of human DCIS and breast cancer suggest that TP53 mutations occur early in DCIS. However, TP53 mutation alone is insufficient for DCIS formation or transformation to invasive disease. Using an autochthonous somatic mouse model of Trp53R245W induced breast cancer (equivalent to the TP53R248W hotspot mutation in humans), we identified DCIS lesions. Through exome sequencing and low-pass whole-genome sequencing, we identified additional genomic changes shared between DCIS and invasive tumors. This comparison nominated seven murine candidate genes, with eight human orthologs. We assessed the cooperativity of these genes with mutant TP53 in human breast cells using acinar morphogenesis and migration assays. Overexpression of TMEM267, which encodes a transmembrane protein overexpressed in 22% of TP53 missense mutant breast cancer cases, in cells with mutant TP53 caused a significant increase in the filled duct, DCIS-like phenotype. We nominate TMEM267 as a cooperating event with mutant TP53 in DCIS progression.

Keywords:  DCIS; breast cancer; mouse models; mutant p53

DOI:  https://doi.org/10.1073/pnas.2526544123