bims-meract 2026-06-07 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–06–07
twenty papers selected by
Andrea Morandi, Università degli Studi di Firenze

Under pressure: peroxisomes in cancer therapy resistance.
Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.
Ferroptosis-based therapeutic strategy targeting iron metabolism and SLC7A11 overcomes oxaliplatin resistance in patient-derived pancreatic cancer organoids.
EZH2 blockade reverses doxorubicin resistance by inducing metabolic vulnerability and enhancing DNA damage in breast cancer.
Targeting taurine metabolism via PROTAC-mediated SLC6A6 degradation potentiates photodynamic therapy and reverses immunosuppression in cholangiocarcinoma.
Targeting GSTZ1 sensitizes KRAS G12C-mutant lung cancer cells by overcoming glutathione and glycolysis pathway rewiring.
AFP Stimulates Glucose Metabolic Reprogramming Contributing to Hepatocellular Carcinoma Resist Sorafenib Through Activating PI3K/AKT Signalling Pathway.
Hyperglycemia promotes O-GlcNAcylation-dependent vulnerability and modulates temozolomide response in glioblastoma.
The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.
Intratumoral bicarbonate functions as an adjuvant to potentiate PD-1 blockade in hepatocellular carcinoma.
BRD4 PROTAC degrader enhances fulvestrant sensitivity in ER+ breast cancer via super-enhancer associated GREB1.
Cholesterol-Mediated Metabolic-mechanotransductive Crosstalk Orchestrates Castration Resistance in Prostate Cancer.
Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy.
Multimodal sequencing identifies synergistic mechanisms driving resistance to neoadjuvant nivolumab treatment in hepatocellular carcinoma.
Mitochondria-targeted OXPHOS inhibition enhances radiotherapy efficacy by disrupting mitochondrial function.
Fuzuloparib enhances radiosensitivity of gain-of-function mutant p53 R273H NSCLC by promoting SLC7A11/GSH/GPX4 axis mediated ferroptosis.
Ceramide-induced endoplasmic reticulum stress reveals a targetable vulnerability in endocrine therapy-resistant breast cancer.
A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells.
Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.
SLC2A1-Dependent Ketone Metabolism Regulates Tumor Progression and Immunotherapy Efficacy in Lung Adenocarcinoma.

Trends Mol Med. 2026 Jun 03. pii: S1471-4914(26)00110-3. [Epub ahead of print]

Under pressure: peroxisomes in cancer therapy resistance.

Nicla Lorito, Francesca Bonechi, Elisabetta Romano, Alfredo Smiriglia, Andrea Morandi.

  Therapy resistance is a major obstacle to durable clinical responses. While genetic alterations and signalling rewiring are primary drivers of resistance, metabolic adaptation, which is closely intertwined with these processes, enables tumour persistence under therapeutic pressure and directly contributes to resistance. Peroxisomes are metabolic organelles with a role in controlling lipid metabolism, together with redox signalling and homeostasis-processes that intersect with pathways governing cancer behaviour and therapy response. Indeed, peroxisomal functions are remodelled to support metabolic plasticity and redox buffering under therapeutic stress. In this review, we synthesise emerging evidence linking peroxisome biology to resistance to chemotherapy, targeted therapies, radiotherapy, and immunotherapy and discuss how peroxisomal pathways may be exploited therapeutically or as biomarkers to overcome cancer therapy resistance.

Keywords:  PPAR; ether phospholipids; fatty acid oxidation; pexophagy; redox homeostasis; therapy resistance

DOI:  https://doi.org/10.1016/j.molmed.2026.05.001
Free Radic Biol Med. 2026 May 30. pii: S0891-5849(26)00827-0. [Epub ahead of print]253 463-477

Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.

Kai Li, Chenggong Luo, Heng Zhang, Ting Yue, Tengda Wang, Yong Ban, Zhaoxuan Li, Xuan Liu, Lingyue An, Guangheng Luo, Zehua Ma.

  Tumor recurrence and therapy resistance are frequently accompanied by alterations in cellular metabolism. However, how metabolic remodeling occurs and contributes to castration-resistant prostate cancer (CRPC) remains largely elusive. Here, we demonstrate that mitochondrial oxidative phosphorylation (OXPHOS) is critical for development of androgen receptor signaling inhibitors (ARSI) resistance. Our findings indicate that prostate cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment. Notably, there is no significant change in glycolytic activity. Importantly, this metabolic remodeling relies on glucose and glutamine utilization. Mechanistically, ARSI treatment activates reactive oxygen species/AMPK/SIRT1/PGC-1α signaling axis, leading to nuclear accumulation of PGC-1α and enhancement of mitochondrial OXHPOS and tricarboxylic acid cycle. High mitochondrial OXPHOS in turn renders prostate cancer cells resistant to ARSI. Inhibitors of PGC-1α and mitochondrial OXPHOS restore drug sensitivity and synergize with ARSI to inhibit CRPC growth. Our findings demonstrate the metabolic plasticity of prostate cancer cells following ARSI treatment, identifying PGC-1α/mitochondrial OXPHOS axis as a potential metabolic target for CRPC treatment.

Keywords:  Androgen receptor signaling inhibitors; Castration-resistant prostate cancer; Metabolic remodeling; Mitochondria; Oxidative phosphorylation; PGC-1α

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.323
J Exp Clin Cancer Res. 2026 May 30.

Ferroptosis-based therapeutic strategy targeting iron metabolism and SLC7A11 overcomes oxaliplatin resistance in patient-derived pancreatic cancer organoids.

Jin Ho Choi, Kyung Min Lee, Minsik Oh, Janghyun Noh, Yooyeon Kim, Eunhye Hwang, In Rae Cho, Woo Hyun Paik, Ji Kon Ryu, Ja-Lok Ku, Sang Hyub Lee.

   BACKGROUND: Oxaliplatin resistance remains a significant challenge in pancreatic cancer (PC) treatment. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has emerged as a promising therapeutic target for overcoming chemotherapy resistance. This study investigated whether ferroptosis induction could overcome oxaliplatin resistance in PC.
METHODS: We established 42 patient-derived pancreatic cancer organoids (PDPCOs) and performed comprehensive molecular profiling including whole-exome sequencing, RNA sequencing and drug response assays. Cell viability, lipid peroxidation, iron levels, mitochondrial function, and drug synergy were evaluated. Survival analysis and differential gene expression analyses were conducted according to the biomarker candidate.
RESULTS: Transcriptomic analysis revealed distinct ferroptosis-related alterations in OXA-resistant PDPCOs, including a negative enrichment of ferroptosis suppressor genes. The ferroptosis inducer artesunate (ART) synergistically enhanced anticancer effects of OXA in cell lines and PDPCOs. Mechanistic studies demonstrated that combination therapy induced ferroptotic cell death by promoting lipid peroxidation, intracellular iron accumulation, and mitochondrial dysfunction. Combination therapy remarkably inhibited tumor growth in PDPCO-derived xenograft models. ART/OXA treatment upregulated expressions of iron transport proteins transferrin receptor (TFRC) and divalent metal transporter 1 (DMT1), contributing to ferroptosis induction. Overexpression of solute carrier family 7 member 11 (SLC7A11) conferred dual resistance to OXA and ART by suppressing ferroptosis, whereas its knockdown or pharmacological inhibition with erastin sensitized resistant cells to combination therapy. Notably, triple combination of ART, OXA, and erastin effectively overcame resistance in dual-resistant PDPCOs.
CONCLUSIONS: Ferroptosis-based therapeutic strategies can overcome oxaliplatin resistance in PC, supporting further investigation of SLC7A11 as a candidate biomarker for ferroptosis-based therapeutic responsiveness.

Keywords:  Biomarker; Drug resistance; Ferroptosis; Organoids; Pancreatic cancer

DOI:  https://doi.org/10.1186/s13046-026-03745-z
Front Pharmacol. 2026 ;17 1786648

EZH2 blockade reverses doxorubicin resistance by inducing metabolic vulnerability and enhancing DNA damage in breast cancer.

Xiaomin Wang, Yuhang Ding, Yunxiao Mai, Ruinan Li, Xinyu Shao, Wenlong Chen, Yiming Li, Luhaoxiang Liu, Haoran Wang, Kangkang Liu, Yuanjie Niu, Jianmin Li, Guoping Xu, Yang Zhao.

   Background: Doxorubicin (DOX) resistance remains a major obstacle to effective chemotherapy in breast cancer. However, the pharmacologically actionable regulators sustaining this resistant phenotype and its therapeutic vulnerabilities remain incompletely defined.
Methods: DOX-resistant breast cancer cell models were established and treated with the EZH2 inhibitors tazemetostat or GSK126, alone or in combination with DOX. Cell viability, oxidative stress, DNA damage, and mitochondrial function were assessed in vitro. Transcriptomic profiling was performed to identify pathway alterations. A pH-responsive liposomal system for delivery of DOX and tazemetostat was developed and evaluated in vivo.
Results: EZH2 was highly expressed in breast cancer and correlated with poor clinical outcomes. DOX treatment induced adaptive upregulation of EZH2 in both sensitive and resistant cells. Pharmacological inhibition of EZH2 markedly restored DOX sensitivity and exhibited strong synergistic cytotoxicity in resistant models. EZH2 blockade enhanced DOX-induced oxidative stress and DNA damage, with concomitant suppression of multiple DNA repair pathways and increased γH2AX accumulation. Transcriptomic and functional analyses revealed disrupted mitochondrial function and energy metabolism, characterized by loss of mitochondrial membrane potential and ATP depletion. In vivo, combined EZH2 inhibition and DOX significantly suppressed tumor growth, while pH-responsive liposomal delivery further enhanced antitumor efficacy and reduced systemic toxicity.
Conclusion: EZH2 is a critical determinant of DOX resistance in breast cancer by sustaining DNA damage tolerance and metabolic homeostasis. Pharmacological targeting of EZH2 in combination with DOX represents a rational strategy to overcome chemoresistance in breast cancer.

Keywords:  DNA damage; EZH2; breast cancer; doxorubicin; metabolic vulnerability; resistance

DOI:  https://doi.org/10.3389/fphar.2026.1786648
J Nanobiotechnology. 2026 Jun 02.

Targeting taurine metabolism via PROTAC-mediated SLC6A6 degradation potentiates photodynamic therapy and reverses immunosuppression in cholangiocarcinoma.

Jingjin Zhu, Tianhao Zou, Weimin Wang, Jianjun Xu, Xuan Li, Lei Liu, Bohan Yang, Zifang Song, Yang Gao.

   BACKGROUND: Photodynamic therapy (PDT) is a promising treatment for cholangiocarcinoma (CCA), but its efficacy is limited by robust tumor antioxidant defenses and immunosuppressive microenvironment. Disrupting the expression of SLC6A6, a taurine transporter critical for redox homeostasis, represents a promising strategy for sensitizing CCA cells to PDT by disrupting taurine-mediated antioxidant protection.
METHODS: A first-in-class antibody-based PROTAC (AbTAC) specifically targeting SLC6A6 degradation was developed, followed by the engineering of biomimetic, ROS-responsive nanoparticles cloaked with CCA cell membranes (CM-TAC@Ce@PEG) for tumor-targeted co-delivery of the AbTAC and the photosensitizer chlorin e6 (Ce6). Comprehensive nanoparticle characterization covered size, drug loading, spectral properties, ROS production, and drug release kinetics. And the CM-TAC@Ce@PEG was evaluated for targeted fluorescence imaging and therapeutic efficacy in vitro and in vivo, with further investigation of its synergy with anti-PD-1 immunotherapy.
RESULTS: Preclinical studies demonstrated that light-induced ROS triggers nanoparticle depolymerization. SLC6A6 degradation depletes taurine in tumor cells, disrupting antioxidant defenses and inducing ferroptosis. Crucially, CM-TAC@Ce@PEG simultaneously induces tumor cells to secrete colony-stimulating factor 2 (CSF2), driving M1 macrophage polarization and restoring CD8⁺ T cell cytotoxicity. This dual action powerfully activates innate and adaptive immunity, significantly inhibiting CCA growth. Furthermore, as a combination therapy with anti-PD-1 immunotherapy, CM-TAC@Ce@PEG markedly enhances therapeutic efficacy and effectively prevents tumor recurrence.
CONCLUSION: This work unveils an integrated strategy that integrating PDT with metabolic reprogramming and immune activation. Targeting SLC6A6-mediated redox dysregulation not only overcomes PDT resistance but also synergizes with immune checkpoint blockade, establishing a promising therapeutic strategy for CCA.

Keywords:  Cholangiocarcinoma; Ferroptosis; Nanoparticles; PROTACs; Photodynamic therapy; Solute carrier

DOI:  https://doi.org/10.1186/s12951-026-04592-y
Cancer Res Commun. 2026 May 20.

Targeting GSTZ1 sensitizes KRAS G12C-mutant lung cancer cells by overcoming glutathione and glycolysis pathway rewiring.

Yi Liao, Xueli Li, Min Liu, Vanessa C Fernandes, Derek Duckett, Eric B Haura, Andrii Monastyrskyi, Uwe Rix.

KRAS mutations are prevalent in lung cancer, but KRAS G12C inhibitors exhibit limited efficacy, partly due to metabolic adaptations, such as enhanced glutathione metabolism and increased glycolysis. Glutathione S-Transferase Zeta 1 (GSTZ1) is a metabolic enzyme that regulates cell metabolism; however, its role in KRAS-driven lung cancer remains underexplored. We recently reported that targeting GSTZ1 significantly enhances the efficacy of FDA-approved KRAS G12C inhibitors in non-small cell lung cancer cells. Untargeted metabolomics now revealed significant alterations in glutathione and glycolytic pathways, marked by lowered lactate levels and increased oxidized glutathione following GSTZ1 ablation. Moreover, pharmacological inhibition of glutathione synthesis and glucose uptake mimicked the sensitizing effects of GSTZ1 targeting. These metabolic shifts were accompanied by increased AMPK phosphorylation and reduced AKT phosphorylation, two key mediators of the response to KRAS G12C inhibition. Our data reveal GSTZ1‑associated metabolic and signaling alterations that contribute to drug resistance and identify GSTZ1 as a potential complementary target to sensitize KRAS mutant NSCLC to KRAS‑directed treatments.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0698
J Cell Mol Med. 2026 Jun;30(11): e71226

AFP Stimulates Glucose Metabolic Reprogramming Contributing to Hepatocellular Carcinoma Resist Sorafenib Through Activating PI3K/AKT Signalling Pathway.

Yuli Zhou, Siren Feng, Yi Chen, Bo Lin, Wei Li, Xu Dong, Kun Liu, Qiushi Yin, Mengsen Li, Mingyue Zhu.

  Alpha fetoprotein (AFP) regulates glucose metabolism reprogramming (GMR) related to drug resistance of hepatocellular carcinoma (HCC) and remains unclear. This study explores the effect of AFP regulating GMR (Glucose metabolic reprogramming) on the tolerance of HCC cells to sorafenib. Thirty clinical liver cancer samples and multi-omics databases were collected; the expression of AFP, GMR-related proteins, pyruvate kinase M2 (PKM2), and the PI3K/AKT signalling pathway-associated proteins were assessed using immunohistochemistry (IHC) or Western blotting. MTT, cloning assays, flow cytometry, and TUNEL were performed to evaluate the effects of AFP on HCC resistance to sorafenib. Alterations in glucose consumption, lactate dehydrogenase activity, and ATP production were measured. Co-immunoprecipitation and immunofluorescence experiments were conducted to determine how AFP interacts with PKM2. An in vivo mouse tumour model was used to investigate the restoration of tumorigenesis and development. The results indicated that AFP inhibited sorafenib-induced apoptosis of HCC cells. AFP activated the PI3K/AKT signalling pathway to promote the GMR-related protein expression and enzyme activity. Particularly, AFP's interaction with PKM2 stimulated the activity of PKM2 to enhance GMR, contributing to HCC resistance to sorafenib. In vivo experiments demonstrated that inhibition of AFP expression attenuated tumorigenesis and growth, and this effect was restored by overexpression of PKM2; PKM2 played a critical activated role in AFP mediating the GMR in HCC. In conclusion, AFP activates the PI3K/AKT signalling pathway to augment aerobic glycolysis in HCC cells, leading to HCC resistance to sorafenib. Inhibition of AFP expression and targeting of PKM2 may represent a novel approach for clinically reversing sorafenib tolerance in HCC patients.

Keywords:  PI3K/AKT signalling pathway; alpha fetoprotein; drug resistance; glucose metabolic reprogramming; hepatocellular carcinoma

DOI:  https://doi.org/10.1111/jcmm.71226
Biochem Biophys Res Commun. 2026 Jun 02. pii: S0006-291X(26)00852-1. [Epub ahead of print]828 154088

Hyperglycemia promotes O-GlcNAcylation-dependent vulnerability and modulates temozolomide response in glioblastoma.

Amanda Vergueiro, Aline Menezes, Natália Rocha, Vivaldo Moura-Neto, Adriane Todeschini, Wagner Barbosa Dias.

Glioblastoma (GB) exhibits metabolic reprogramming influenced by systemic conditions such as hyperglycemia. Here, we investigated whether glycemic status modulates glycosylation pathways and therapeutic response in patient-derived GB cells. Hyperglycemia was associated with increased expression of hexosamine biosynthetic pathway (HBP) enzymes (GFAT1/2) and O-GlcNAcylation machinery (OGT/OGA), correlating with blood glucose levels and defining distinct metabolic profiles. In contrast, N-glycosylation-related enzymes showed heterogeneous regulation. Functionally, inhibition of O-GlcNAcylation reduced cell viability and enhanced sensitivity to temozolomide (TMZ), particularly in cells derived from hyperglycemic patients. These findings indicate that hyperglycemia promotes a glycosylation-dependent metabolic adaptation while creating a targetable vulnerability. Targeting O-GlcNAcylation may improve therapeutic response in hyperglycemia-associated glioblastoma.

DOI: https://doi.org/10.1016/j.bbrc.2026.154088
Nat Commun. 2026 Jun 03.

The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.

Hussein Issaoui, Lina Zawil, Lola Bellone, Diogo Goncalves, Rachel Paul, Léa Di Mascio, Sonia Núñez-Vázquez, Sandrine Marchetti, Johanna Chiche, Nicolas Nottet, Simon Le Goupil, Hadrien Laprade, Lucile Bansard, Yourae Hong, Rebecca Wall, Sabine Tejpar, Caroline Truntzer, François Ghiringhelli, Suresh Poudel, Helen M Beere, Douglas R Green, Julie Pannequin, Eric Chevet, Jean-Ehrland Ricci.

Most colorectal cancer (CRC) patients exhibit resistance to immune checkpoint blockade (ICB), limiting treatment efficacy. Activating the unfolded protein response sensor IRE1α in cancer cells can induce anticancer immune responses, yet its regulation remains unclear. Here we identify Dolichyl-Phosphate Mannosyltransferase 1 (DPM1) as a regulator of IRE1 expression and activity using BioID screen. Analysis of CRC patient RNA-sequencing data reveals that low DPM1 expression correlates with an IRE1-dependent transcriptional signature, increased immune infiltration, and improved ICB responses. Mechanistically, DPM1 ablation reduces protein glycosylation, causing chronic IRE1 activation in cancer cells and enhanced cytotoxic T cell-mediated immunosurveillance. Inhibition or knock-out of IRE1 reverses this effect. These findings establish DPM1 as a modulator of IRE1 activity that influences tumor immunogenicity, suggesting its potential as a therapeutic target to improve cancer immunotherapy outcomes.

DOI: https://doi.org/10.1038/s41467-026-73942-z
Oncogene. 2026 Jun 05.

Intratumoral bicarbonate functions as an adjuvant to potentiate PD-1 blockade in hepatocellular carcinoma.

Di Wang, Kai Jin, Chang Ying, Bin Li, Guangqiang Zhang, Jiangtao Li, Lirong Chen, Ming Chao, Xun Hu.

AntiPD-1 immunotherapy improves survival in advanced hepatocellular carcinoma (HCC), but responses remain limited by the immunosuppressive, acidic tumor microenvironment (TME). We investigated whether intratumoral alkalization with sodium bicarbonate could enhance PD-1 blockade. Bicarbonate-induced intracellular alkalization disrupted mitochondrial membrane potential, triggered rupture, and activated the cGAS-STING pathway via cytosolic mitochondrial DNA release, while simultaneously inducing immunogenic cell death (ICD). In murine models, intratumoral bicarbonate recruited and activated dendritic cells and T cells, suppressing tumor growth and synergizing with antiPD-1 therapy. In a prospective clinical study (ChiCTR2100053537), 28 patients with advanced-stage and 2 with intermediate-stage HCC received Tislelizumab plus intratumoral 5% sodium bicarbonate. The objective response rate was 93.3% (CR 53.3%, PR 40.0%); median progression-free survival was 31 months, and median overall survival was not reached. Treatment was well tolerated. Biopsies revealed significantly increased CD3⁺, CD4⁺, and CD8⁺ T-cell infiltration with combination therapy versus Tislelizumab alone. In line with our previous work, through this mitochondria-centered mechanism bicarbonate links metabolic reprogramming with innate and adaptive immune activation. Thus, intratumoral bicarbonate functions as a safe and accessible immunometabolic adjuvant that markedly enhances PD-1 blockade efficacy in HCC.

DOI: https://doi.org/10.1038/s41388-026-03836-3
Front Oncol. 2026 ;16 1828900

BRD4 PROTAC degrader enhances fulvestrant sensitivity in ER+ breast cancer via super-enhancer associated GREB1.

Xiulei Zhang, Peiming Zheng, Zhengyi Liu, Qian Zhang, Wenjing Duan, Tingting Zhang, Xiaozhuan Liu.

   Background: Breast cancer has the highest incidence and mortality among all cancers affecting women. Fulvestrant resistance remains a major clinical challenge that limits the efficacy of endocrine therapies. BRD4, a transcriptional regulator that recognizes acetylated histones, is implicated in the pathogenesis and progression of various tumors, including breast cancer. However, its role in fulvestrant sensitivity and the therapeutic potential of targeted BRD4 degradation require further investigation.
Methods: We assessed BRD4 transcriptional activity in breast cancer and its functional role in tumor progression and endocrine sensitivity. The antitumor effect of a PROTAC-targeted BRD4 degrader, alone or in combination with fulvestrant, was evaluated in breast cancer cells. Integrated analysis of BRD4 and estrogen receptor (ER) chromatin immunoprecipitation sequencing (ChIP-seq) datasets was performed to identify co-occupied genomic regions and downstream targets. GREB1 was identified as a key effector and further validated as a super-enhancer-associated gene. The working mechanism of BRD4 PROTAC and fulvestrant was investigated through GREB1 signaling disruption.
Results: The occupancy of BRD4 at promoter regions was found to be increased in breast cancer, and its high expression indicated poor clinical outcome among ER+ breast cancer patients with endocrine therapy. A PROTAC-targeted BRD4 degrader significantly enhanced the antitumor efficacy of fulvestrant in breast cancer cells. Integrated ChIP-seq analysis revealed substantial co-occupancy of BRD4 and ER on shared pathways and identified GREB1 as a critical downstream effector regulated by a BRD4-associated super-enhancer. Mechanistically, the BRD4 PROTAC enhances fulvestrant sensitivity by down-regulation of GREB1 expression.
Conclusion: Targeting BRD4 with PROTAC degraders represents a promising therapeutic strategy in breast cancer by suppressing GREB1 expression and enhancing the efficacy of fulvestrant.

Keywords:  BRD4; GREB1; PROTAC; breast cancer; fulvestrant sensitivity

DOI:  https://doi.org/10.3389/fonc.2026.1828900
Adv Sci (Weinh). 2026 Jun 04. e75977

Cholesterol-Mediated Metabolic-mechanotransductive Crosstalk Orchestrates Castration Resistance in Prostate Cancer.

Shaojie Liu, Chao Xu, Jun Jiang, Limin He, Yike Zhou, Zhengxuan Li, Yu Li, Keying Zhang, Fa Yang, Tong Lu, Hongtao Song, Hai Zhu, Zhihao Hu, Xiaolong Zhao, Kai Gan, Hongji Li, Bo Yang, Rui Zhang, Weihong Wen, Donghui Han, Weijun Qin.

  Biophysical microenvironment fuels therapeutic resistance, yet the contribution of matrix stiffness to castration-resistant prostate cancer (CRPC) remains poorly understood. In this study, we established a metabolic-mechanotransductive crosstalk wherein cholesterol-driven stromal reprogramming amplifies CRPC progression. Mechanistically, full androgen deprivation (FAD) induces cholesterol metabolic rewiring in prostate cancer (PCa) cells that orchestrates the CH25H-dependent phenotype transformation of cancer-associated fibroblast (CAF) into myofibroblastic CAF (myCAF). In turn, the resulting matrix stiffness induces unfolded protein response (UPR) and potentiates IRE1α kinase activity for Xbp1 splicing, while concurrently activating the integrin αVβ3/FAK/STAT3 axis to transcriptionally replenish Xbp1 substrate in PCa cells. This mechanosensitive adaptation thereby confers PCa with resistance to apoptosis induced by FAD. Consequently, pharmacological disruption of this metabolic-mechanotransductive axis by targeting cholesterol metabolism or blockade of IRE1α-XBP1s signaling significantly suppress tumor growth, representing a promising therapeutic strategy for CRPC progression.

Keywords:  CRPC; cancer associated fibroblast; cholesterol; matrix stiffness; mechanotransduction

DOI:  https://doi.org/10.1002/advs.75977
JCI Insight. 2026 Jun 04. pii: e203777. [Epub ahead of print]

Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy.

Rodney Claude, Sankalp Srivastava, Kirk A Staschke, Carlos A Mellado Fritz, Shaoxiong Chen, Lei Liu, Minghua Zhong, Harish Kothandaraman, Nadia A Lanman, Utpal P Davé, Sandeep Batra, Jiehao Zhou, Yue Fang, Chi Zhang, Reuben Kapur, Jing Fan, Ronald C Wek, Ji Zhang.

  Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B- and T-cell lineages. Current therapy exploits ALL cells' low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and a novel ASNS inhibitor designated ASX-173. Using a KrasG12D-driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of Gcn2-/- T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS-high leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.

Keywords:  Amino acid metabolism; Cell stress; Hematology; Leukemias; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.203777
Mol Cancer. 2026 Jun 01.

Multimodal sequencing identifies synergistic mechanisms driving resistance to neoadjuvant nivolumab treatment in hepatocellular carcinoma.

Fanhong Zeng, Jiaxin Guo, Zheng Zeng, Vanilla Xin Zhang, Yu-Man Tsui, Po-Man Li, Abdullah Husain, Qingyang Zhang, Joyce Man-Fong Lee, Tan-To Cheung, Daniel Wai-Hung Ho, Irene Oi-Lin Ng.

  The tumor immune microenvironment (TIME) critically modulates therapeutic responses to immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). Relative to the other solid tumors, HCC is characterized by more pronounced intratumoral heterogeneity and has comparatively poorer responsiveness to ICI blockade treatment. Importantly, the correlation of the underlying mechanism of TIME and the molecular underpinnings of immunotherapy resistance in HCC remains elusive. Employing an integrative multi-omics approach, including spatially resolved transcriptomics, single-cell and bulk RNA sequencing, and lipidomics, we delineated the spatiotemporal dynamics and mechanistic basis of resistance to anti-PD-1 therapy in HCC. Our analyses revealed a profoundly immunosuppressive TIME in non-responsive patients, marked by sparse immune cell infiltration within the tumor niche, in contrast to the immune-inflamed TIME observed in the responders. Multidimensional profiling further uncovered dysregulated lipogenesis and aberrant lipid accumulation in tumor cells of the non-responder cases. Notably, tumor-associated macrophages (TAMs), exhausted CD8 T cells, and lipid-enriched tumor cells co-localize at the tumor-immune interface, forming a physical and functional barrier that precludes effective immune cell infiltration into the tumor niche. We also identified the pivotal TAM-tumor cell crosstalk via the ADM-RAMP1-EBP signaling axis, orchestrating lipid metabolism reprogramming and contributing to the attenuated PD-1 therapeutic efficacy. Collectively, these findings provide a comprehensive mechanistic framework for anti-PD1 resistance, unveiling actionable biomarkers and a translational vulnerability to enhance precision therapeutics in HCC.

Keywords:  Immunotherapy; Lipid metabolism; Liver cancer; Spatial transcriptomics

DOI:  https://doi.org/10.1186/s12943-026-02682-x
Radiother Oncol. 2026 Jun 03. pii: S0167-8140(26)00456-1. [Epub ahead of print] 111617

Mitochondria-targeted OXPHOS inhibition enhances radiotherapy efficacy by disrupting mitochondrial function.

Anne P M Beerkens, Paolo S Taracatac, Wenny J M Peeters, Johannes P W Peters, Gosse J Adema, Sandra Heskamp, Johan Bussink, Paul N Span.

   INTRODUCTION: Reducing tumor cell oxygen consumption has emerged as a promising strategy to counter hypoxia-induced radioresistance in solid tumors. Previously, we found that OXPHOS inhibition using PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) and mitochondria-targeted tamoxifen (MitoTam) alleviated hypoxia in tumor spheroids. Here, we investigated the underlying metabolic and redox-related mechanisms-of-action and examined whether mitochondria-targeted OXPHOS inhibition enhances radiotherapy (RT)-induced DNA damage.
METHODS: The metabolic and redox-related effects of Mito-PEG-ATO and MitoTam alone or combined with RT were examined in B16OVA, MOC1.3D5 and MC38 cells or clones containing an HRE-eGFP-ODD construct. Viability was assessed using a CCK-8 assay on 2D cells. ROS levels were measured after treatment with Mito-PEG-ATO and MitoTam for 24 h with CellRox green and fluorescence monitoring via IncuCyte Zoom. Antioxidant capacity was measured after OXPHOS inhibition relative to Trolox, an analogue of Vitamin E used as antioxidant standard, and mitochondrial membrane potential (MMP) was examined using MitoTracker Orange. Intracellular ATP and metabolic dehydrogenase activity was assessed in tumor spheroids via CellTiter-Glo and CCK-8 assays. Viability, MMP, ATP levels and metabolic activity were measured at 4 h and 24 h post-RT. DNA damage was quantified by γH2AX immunofluorescence in spheroids. Tumor hypoxia following treatment with Mito-PEG-ATO was determined with immunohistochemistry in MOC1.3D5 tumor-bearing mice.
RESULTS: Mito-PEG-ATO and MitoTam reduced cell viability independent of hypoxia and increased ROS production, which was most pronounced for Mito-PEG-ATO, while no effect was observed on antioxidant capacity. Mitochondrial function was impaired by OXPHOS inhibition, shown by MMP disruption, ATP depletion and reduced metabolic activity, with no further impairment upon combination with RT. However, combining Mito-PEG-ATO or MitoTam with RT increased DNA damage compared to either treatment alone. Treatment with Mito-PEG-ATO in MOC1.3D5 tumor-bearing mice did not alleviate hypoxia or alter lactate levels.
CONCLUSION: Mito-PEG-ATO and MitoTam increase ROS production and disrupt mitochondrial function, enhancing RT-induced DNA damage and potentially improving RT efficacy. However, mice treated with Mito-PEG-ATO did not show a reduction in tumor hypoxia.

Keywords:  Antioxidant capacity; Hypoxia; Mito-targeted OXPHOS inhibitors; ROS; Radio sensitivity; Radiotherapy

DOI:  https://doi.org/10.1016/j.radonc.2026.111617
NPJ Precis Oncol. 2026 Jun 01.

Fuzuloparib enhances radiosensitivity of gain-of-function mutant p53 R273H NSCLC by promoting SLC7A11/GSH/GPX4 axis mediated ferroptosis.

Mengjia Wu, Chaoyuan Pu, Wanxuan Weng, Fengmin Yin, Lei Zhang, Chenggang Xu, Mingjian Li, Chuanhui Cao, Wei Hu.

Radiotherapy is a crucial therapeutic approach for the management of non-small cell lung cancer (NSCLC). Nevertheless, the radioresistance of NSCLC, particularly in cases involving the gain-of-function mutant p53, substantially limits its efficacy. According to recent research, mutant p53 R273H can recruit poly (ADP-ribose) polymerase (PARP)-1 on replicating DNA to promote tumor survival. Whether mutant p53 R273H-mediated radioresistance is related to the interaction between mutant p53 R273H and PARP1, and if PARP1 inhibitors (PARPi) can increase the radiosensitivity of mutant p53 R273H-expressing tumors have not been explored. Through in vitro and in vivo experiments, we determined that mutant p53 R273H promotes radioresistance in NSCLC by partially inhibiting ferroptosis through the SLC7A11/GSH/GPX4 axis, independently of PARP1, whereas FZ counteracts this effect by partially blocking the same axis to promote ferroptosis, presenting a potential novel strategy for treating NSCLC patients with gain-of-function mutant p53 R273H.

DOI: https://doi.org/10.1038/s41698-026-01526-7
Mol Cancer Res. 2026 Jun 03.

Ceramide-induced endoplasmic reticulum stress reveals a targetable vulnerability in endocrine therapy-resistant breast cancer.

Purab Pal, Shweta Chitkara, Godwin K Sarpey, Aanshi Vashi, Vipin Rawat, Fatimah Alani, Huiping Zhao, Malik Ata, Jun Qu, Rachel Schiff, Debra Tonetti, Geoffrey L Greene, Jonna Frasor, Gunes Ekin Atilla-Gokcumen, Jonathan L Coloff.

Despite the success of endocrine therapy (ET) in treating hormone receptor-positive breast cancer, a significant proportion of patients relapse during or after treatment, making ET resistance a major clinical challenge. Previously we have shown that ET-resistant breast cancer cells exhibit reduced ceramide levels and an increased sensitivity to ceramide-induced cell death. Here, we demonstrate that ceramides induce a distinct transcriptional reprogramming in ET-resistant cells, characterized by upregulation of endoplasmic reticulum stress (EnRS) pathways. Ceramide-induced EnRS is PERK-dependent and functionally linked to cell death in multiple models of ET resistance. Using a photoactivatable ceramide probe, we identify TRAM1 as a functionally important ceramide-interacting protein (CIP) in ET-resistant cells that correlates with worse relapse-free survival and a more aggressive breast cancer phenotype in luminal breast cancer patients. Additionally, knockdown of TRAM1 phenocopies ceramide action in ET resistance, thereby suggesting its role in mediating ceramide-induced lethal actions in ET resistance. Together, our findings reveal that ET-resistant breast cancer cells are highly sensitive to PERK-mediated EnRS relative to ET-sensitive cells. Ceramides, likely via interactions with CIPs such as TRAM1, lead to PERK activation and consequential cell death in the ET-resistant breast cancer models. This sensitivity to ceramide-induced EnRS and cell death is a vulnerability that could be taken advantage of to treat ET-resistant breast cancer. Implications: This study elucidates the functional relevance of ceramide depletion in endocrine therapy-resistant breast cancer cells.

DOI: https://doi.org/10.1158/1541-7786.MCR-25-0964
Mol Cancer Ther. 2026 Jun 02.

A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells.

Nisha R Pawar, Heidi M Wade, Zoe Jackson, Nisha Poungpeth, Allison V Mitchell, Connor P Jewell, Dalen Chan, Pedro J Batista, Robert W Robey, Lisa M Jenkins, Michael M Gottesman.

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, with a five-year survival rate of 65%. Oxaliplatin was the first platinum drug shown to improve CRC patient outcomes and is now a common adjuvant therapy for advanced disease, yet 90% of patients develop resistance. Oxaliplatin was developed as a third-generation derivative of cisplatin, but recent evidence points to divergent modes of action. Here, genome-wide CRISPR activation and knockout screens were conducted to identify genetic changes that confer resistance to oxaliplatin in two CRC cell lines with distinct molecular backgrounds (SW620 and RKO). Guide RNAs corresponding to the neutral amino acid transporter SLC43A1 (LAT3) were the most significantly enriched in knockout screens and depleted in activation screens, suggesting a potential role for LAT3 in modulating oxaliplatin resistance. In vitro CRISPR knockout and overexpression of LAT3 in SW620 and RKO cell lines confirm increased resistance or sensitivity to oxaliplatin, respectively. Further analysis demonstrates that increased LAT3 levels corrrelate with increased intracellular levels of oxaliplatin, and increased levels of DNA-platinum adducts and DNA damage, demonstrating that enhanced LAT3-mediated uptake of oxaliplatin can exert its expected mechanism of action and induce cytotoxicity. These findings may lead to a better understanding of oxaliplatin's mode of action in CRC and can provide new insights into the interplay between essential nutrient uptake and drug transport.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0508
Leukemia. 2026 Jun 02.

Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.

Aditi Chatterjee, Moaath K Mustafa Ali, Christopher M Bailey, Yuchen Liu, Donald Small, Catherine C Smith, Elie Traer, Yin Wang, Giovannino Silvestri, Maria R Baer.

FLT3 inhibitor efficacy in AML with FLT3-ITD is short-lived, frequently due to new mutations, most commonly in NRAS. Sphingosine kinase 1 (SPHK1), which phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), is upregulated and localized to the plasma membrane in RAS-mutated cells. We studied S1P and FLT3 co-targeting to overcome FLT3 inhibitor resistance in NRAS-mutated FLT3-ITD AML cells. NRAS-mutated FLT3-ITD AML cell lines and patient blasts were treated with FLT3 inhibitors and/or S1P receptor (S1PR) modulators. FLT3 inhibitor sensitivity was assessed by immunoblotting, cytotoxicity, apoptosis and colony formation. Co-treatment was also assessed in vivo in an orthotopic mouse model. Downstream RAS and SPHK1 effectors were measured by immunoblotting and qRT-PCR. The S1PR modulators fingolimod (FTY720) and mocravimod (KRP-203) resensitized FLT3-ITD-expressing MOLM-14 and MV4-11 human AML cells with G12D, G12S, Q61K or Q61H, but not G12C, and patient blasts with G13D, G13V or G12D NRAS mutations to FLT3 inhibitors. Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70 S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy.

DOI: https://doi.org/10.1038/s41375-026-02982-7
Crit Rev Immunol. 2026 ;46(2): 59-76

SLC2A1-Dependent Ketone Metabolism Regulates Tumor Progression and Immunotherapy Efficacy in Lung Adenocarcinoma.

Xing Feng, Li Gao, Yonggang Xue, Yanbing Zhang, Hongyou Cao, Tianchang Wange.

The aim of this study is to identify and validate ketogenesis-immune cross-talk genes with prognostic significance in LUAD patients. Bulk RNA-seq data of LUAD were obtained from TCGA and GEO databases to analyze differentially expressed genes (DEGs), which were intersected with ketogenesis-related gene sets from MSigDB. DEGs associated with anti-PD-1 therapy sensitivity were further identified. Univariate and multivariate Cox regression analyses were performed to determine independent prognostic genes. Molecular subtypes and an 8-gene ketogenesis-immune prognostic signature were constructed and validated. Single-cell RNA-seq data were used to map cell-type-specific expression of prognostic genes. Functional effects of SLC2A1, a key metabolic regulator, were evaluated in A549 cells using overexpression/knockdown approaches combined with β-hydroxybutyrate (BHB) treatment. A total of 135 ketogenesis-immune cross-talk genes were identified. Consensus clustering defined two LUAD subtypes with distinct prognosis and immune landscapes. Single-cell analysis revealed SLC2A1 enrichment in epithelial tumor cells. Functional assays showed that SLC2A1 overexpression enhanced proliferation, migration, glycolysis, and ATP production, whereas knockdown suppressed these processes; BHB partially rescued energy deficits in SLC2A1-deficient cells. Mechanistically, SLC2A1 regulated ketone-body utilization and AMPK/mTOR signaling, linking metabolic reprogramming with tumor growth and immune modulation. SLC2A1 is a critical regulator of ketone-body metabolism in LUAD and serves as a potential prognostic factor.

DOI: https://doi.org/10.1615/CritRevImmunol.2026062879