bims-meract 2025-11-09 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2025–11–09
fifteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Diet-metabolism-transcription axis modulates the sensitivity to CDK4/6 inhibitors through RB1 in prostate cancer.
ESR1 Activating Mutations Confer Metabolic Vulnerabilities in ER+ Breast Cancer.
USP2-mediated PPARγ stabilization promotes hepatocellular carcinoma progression and M2 macrophage polarization via oleic acid.
JMJD3 upregulates ALOX5 to drive malignancy and concomitant ferroptosis sensitivity in gastric cancer.
Crosstalk between lipid droplets and autophagy in cancer: A nexus for therapeutic targeting.
Characterization of Drug-Tolerant Persister Cells in Triple-Negative Breast Cancer Identifies a Shared Persistence Program across Treatments and Patients.
Novel Strategies against Hepatocellular Carcinoma through Lipid Metabolism.
Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.
CypA Mediates Non-Small Cell Lung Cancer Chemoresistance by Attenuating Ferroptosis via Stabilizing SLC7A11.
Lactylation in Cancer: Unlocking the Key to Drug Resistance and Therapeutic Breakthroughs.
Nanoparticles-mediated mitochondrial relocation of lipid-lowering drugs shape energy metabolism to conquer acquired immune resistance.
A novel strategy to target metabolic dependencies in acute myeloid leukemia.
Restoration of cGAS in cancer cells promotes antitumor immunity via transfer of cancer cell-generated cGAMP.
PHF10 is a Novel Substrate of Keap1 to Protect Non-Small-Cell Lung Cancer (NSCLC) Cells Against Oxidative Stress and Confer Ferroptosis Resistance.
Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver.

Cell Rep. 2025 Nov 05. pii: S2211-1247(25)01301-4. [Epub ahead of print]44(11): 116530

Diet-metabolism-transcription axis modulates the sensitivity to CDK4/6 inhibitors through RB1 in prostate cancer.

Xurui Li, Zhenghui Sun, Ruijiang Zeng, Ruiling Liu, Pingxia Lin, Zhuo Xing, Xin Jin, Tiejun Yang.

  A high-fat diet (HFD) promotes tumor progression and therapeutic resistance, but its mechanistic role in prostate cancer (PCa) remains unclear. In this study, we show that an HFD not only accelerates PCa progression but also significantly reduces sensitivity to CDK4/6 inhibitors. Mechanistically, an HFD activates CDK4, inducing RB1 phosphorylation and facilitating E2F1 release. Meanwhile, phosphorylation of RB1 at the S249/T252 site enhances its interaction with ETS1 and suppresses ETS1's transcriptional activity. Treatment with CDK4/6 inhibitors induces dephosphorylation at this site, relieving ETS1 suppression and promoting PCYT2 expression and phosphatidylcholine metabolic reprogramming. The resulting metabolic products further disrupt RB1-E2F1 binding, leading to additional E2F1 release and increased resistance to CDK4/6 inhibitors. In conclusion, our results identify a diet-metabolism-transcriptional regulatory axis centered on RB1 phosphorylation and ETS1 reactivation, reveal a mechanism of acquired resistance to CDK4/6 inhibitors of castration-resistant PCa, and provide a theoretical basis for combinatorial strategies targeting metabolic and oncogenic signals.

Keywords:  CDK4/6 inhibitors; CP: cancer; CP: metabolism; RB1; high-fat diet; prostate cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.116530
Cancer Res. 2025 Nov 07.

ESR1 Activating Mutations Confer Metabolic Vulnerabilities in ER+ Breast Cancer.

Francesca Bonechi, Marina Bacci, Nicla Lorito, Alfredo Smiriglia, Angela Subbiani, Edoardo Pagliantini, Giuseppina Comito, Giulia Gangarossa, Assia Duatti, Rania El Botty, Laura Sourd, Elisabetta Romano, Gabriele Tani, Ilenia Segatto, Barbara Belletti, Icro Meattini, Lorenzo Livi, Bruna Cerbelli, Andrea Botticelli, Marco Fiorillo, Elisabetta Marangoni, Andrea Morandi.

Endocrine therapy (ET) is the standard of care for estrogen receptor-positive (ER+) breast cancer. Point mutations in the ligand-binding domain of the gene encoding the estrogen receptor (ESR1) are rare in naïve ER+ breast cancer while becoming common in the ET-resistant setting. Here, we found that ESR1 mutations expose breast cancers to critical vulnerabilities related to lipid metabolism. Particularly, ESR1 mutations that induce constitutive ER activation drove aberrant lipid biogenesis and lipid upload in parallel with increased expression of the acyl-CoA synthetase long-chain family member 4 (ACSL4), which has a crucial role in fatty acid activation and has been shown to correlate with increased ferroptosis susceptibility. While ER+ breast cancer cells displayed ferroptosis resistance, the presence of ESR1 mutations rendered tumor cells sensitive to ferroptosis induction. Importantly, ferroptosis inducers potentiated the effects of the selective estrogen receptor degraders fulvestrant and elacestrant, which are the standard of care for breast cancers carrying ESR1 mutations. These findings, validated both in preclinical models and in patient-derived material, identify a combinatory therapeutic approach in the setting of ET resistance and establish ACSL4 as an important biomarker to recognize ER+ breast cancers susceptible to ferroptosis induction.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1339
J Immunother Cancer. 2025 Nov 04. pii: e012721. [Epub ahead of print]13(11):

USP2-mediated PPARγ stabilization promotes hepatocellular carcinoma progression and M2 macrophage polarization via oleic acid.

Jing Cao, Kui Chen, Kuan Hu, Xingyu Mi, Yilin Pan, Desheng Xiao, Shuang Liu, Liang Xiao, Ledu Zhou, Yongguang Tao, Jianing Tang.

   BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive liver cancer with poor prognosis. Deubiquitinating enzymes (DUBs) are critical regulators of tumor progression, yet the functional significance of DUBs in HCC remains poorly understood.
METHODS: HCC patient-derived organoids (PDOs), HCC cell lines and animal models were used to evaluate the anticancer responses of ubiquitin-specific protease (USP)2 inhibition. We analyzed the correlation of USP2 expression and immune cells infiltration using single-cell RNA sequencing and flow cytometry analysis. Mechanistically, we established an in vitro co-culture system and analyzed metabolic data to find out the bridge between tumor cell USP2 and macrophage in the microenvironment. Immunofluorescence, co-immunoprecipitation, CUT&RUN, ELISA, and mass spectrometry were conducted to explore the molecular pathway.
RESULTS: We found that the inhibitor (ML364) targeting USP2 shows effective anticancer responses against HCC PDOs. Targeting USP2 significantly inhibits lipid metabolism of HCC and induces cell ferroptosis. Single-cell RNA sequencing analysis and multiplex immunohistochemistry analysis indicated that high expression of USP2 in HCC was associated with the infiltration of M2 macrophage. Mechanistically, USP2 deubiquitinates and stabilizes peroxisome proliferator-activated receptor gamma (PPARγ) via removing the K48-linked ubiquitin chain at the K142 site. PPARγ promotes the transcription of fatty acid biosynthesis-related genes (ATP-citrate lyase, acetyl-CoA carboxylase and ACSS2) and de novo synthesis of fatty acids including oleic acid. HCC cell-derived oleic acid promotes M2 macrophage polarization by enhancing the fatty acid oxidation of macrophages. Polarized M2 macrophages further secrete interleukin-10, which created an IL-10/STAT3/USP2 positive-feedback loop to activate USP2 expression continuously.
CONCLUSION: Our data suggest that USP2, a key molecule mediating the interaction between HCC cells and tumor-associated macrophages, may be a promising therapeutic target for HCC.

Keywords:  Immunotherapy; Macrophage

DOI:  https://doi.org/10.1136/jitc-2025-012721
Cell Death Dis. 2025 Nov 03. 16(1): 782

JMJD3 upregulates ALOX5 to drive malignancy and concomitant ferroptosis sensitivity in gastric cancer.

Gege Shu, Jiaoyang Yang, Huifang Hu, Anqi Dong, Tao Chen, Weikang Li, Xiaotong Sun, Peiyuan Li, Pengbo Wang, Changshun Shao, Jin Zhou.

Chemotherapy remains the cornerstone of gastric cancer (GC) treatment, with Oxaliplatin (OXA) being a critical first-line agent. However, chemotherapy resistance, compounded by increased stemness, poses a significant challenge in GC management. In this study, we demonstrate that JMJD3, encoded by KDM6B and catalyzing the demethylation of H3K27me3, is highly expressed in both GC tissues and patient-derived chemotherapy-resistant xenograft (PDX) models and contributes to increased malignancy and chemoresistance. Overexpression of JMJD3 enhanced stemness and chemoresistance in GC cells, while JMJD3 knockdown had opposite effects. Mechanistically, JMJD3 promotes GC cell stemness and chemoresistance by reducing H3K27me3 on the ALOX5 promoter, a histone modification associated with ALOX5 transcriptional activation. Tumorigenesis induced by N-methyl-N-nitrosourea (MNU) was reduced in mice with gastric epithelial cell-specific deletion of Kdm6b. Importantly, ALOX5 upregulation due to the elevated JMJD3 function sensitized GC cells to ferroptosis inducers. These findings suggest that JMJD3 plays a pivotal role in GC chemoresistance by modulating both stemness and ferroptosis sensitivity. Targeting JMJD3 may provide a novel therapeutic strategy for overcoming chemotherapy resistance, with ferroptosis inducers potentially offering a promising adjunctive treatment in GC.

DOI: https://doi.org/10.1038/s41419-025-08020-1
Pharmacol Res. 2025 Nov 04. pii: S1043-6618(25)00448-7. [Epub ahead of print]222 108023

Crosstalk between lipid droplets and autophagy in cancer: A nexus for therapeutic targeting.

Xiaofen Li, Jiwen Zhang, Shiping Luo, Xiaoqin Yu, Chuangui Song.

  Metabolic reprogramming is a cornerstone of cancer cell adaptation to the demanding tumor microenvironment, requiring fine-tuned control over energy, lipid metabolism, and stress responses. Central to this adaptation is the profound and bidirectional interplay between two key cellular processes: lipid storage in lipid droplets (LDs) and cellular recycling via autophagy. LDs are dynamic organelles that have emerged as critical metabolic and signaling hubs, extending far beyond their role as simple lipid depots. Autophagy, a fundamental degradation system, supplies essential metabolites during stress by engulfing cellular material in autophagosomes. These pathways are deeply intertwined: LDs not only provide lipids and proteins for autophagosome formation but are also selectively targeted for degradation by autophagy in a process known as lipophagy. This degradation releases free fatty acids that fuel mitochondrial β-oxidation, enabling cancer cells to withstand hypoxic and nutrient-poor conditions. Moreover, lipophagy prevents lipotoxicity by eliminating excess lipids, thus maintaining cellular homeostasis. Here, we review the molecular mechanisms governing the LD-autophagy axis in cancer, discuss its pivotal roles in tumor progression, metastasis, and therapeutic resistance, and explore the promise of targeting this nexus for future cancer therapies. Unraveling this complex network provides not only a new paradigm for understanding cancer metabolism but also offers a compelling rationale for developing novel pharmacological agents to combat tumor metabolic plasticity and therapeutic resistance.

Keywords:  Autophagy; Cancer Therapy; Lipid Droplets; Lipophagy; Metabolic Reprogramming; Tumor Microenvironment

DOI:  https://doi.org/10.1016/j.phrs.2025.108023
Cancer Res. 2025 Nov 06. OF1-OF16

Characterization of Drug-Tolerant Persister Cells in Triple-Negative Breast Cancer Identifies a Shared Persistence Program across Treatments and Patients.

Léa Baudre, Grégoire Jouault, Pacôme Prompsy, Melissa Saichi, Sarah Gastineau, Christophe Huret, Laura Sourd, Ahmed Dahmani, Elodie Montaudon, Florent Dingli, Damarys Loew, Elisabetta Marangoni, Justine Marsolier, Céline Vallot.

Acquisition of resistance to anticancer therapies is a multistep process initiated by the survival of drug-tolerant persister cells. Accessibility of drug-tolerant persister cells in patients is limited, which has hindered understanding the mechanisms driving their emergence. In this study, using multiple patient-derived models to isolate persister cells, we showed that these cells are transcriptionally plastic in vivo and return to a common treatment naïve-like state upon relapse, regardless of treatment. Hallmarks of the persister state in triple-negative breast cancer (TNBC) across treatment modalities included high expression of basal keratins together with activation of stress response and inflammation pathways. These hallmarks were also activated in HER2+ breast and lung cancer cells in response to targeted therapies. Analysis of gene regulatory networks identified AP-1, NF-κB, and IRF/STAT as the key drivers of this hallmark persister state. Functionally, FOSL1, an AP-1 member, drove cells to the persister state by binding enhancers and reprogramming the transcriptome of cancer cells. On the contrary, cancer cells without FOSL1 had a decreased ability to reach the persister state. By defining hallmarks of TNBC persistence on multiple therapies, this study provides a resource to design effective combination therapeutic strategies that limit resistance.
SIGNIFICANCE: Elucidation of the features of the drug-tolerant persister state in triple-negative breast cancer reveals shared programs across patients and treatments that offer opportunities to prevent persistence and delay tumor recurrence.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0995
Oncol Res. 2025 ;33(11): 3247-3268

Novel Strategies against Hepatocellular Carcinoma through Lipid Metabolism.

Yuanyuan Yang, Peipei Zhao, Hepu Chen, Yixuan Tu, Yujia Zhou, Xu Liu, Lyly Sreang, Zhigang Zhou, Jian Tu.

  Hepatocellular carcinoma (HCC) is characterized by its highly invasive and metastatic potential, as well as a propensity for recurrence, contributing to treatment failure and increased mortality. Under physiological conditions, the liver maintains a balance in lipid biosynthesis, degradation, storage, and transport. HCC exhibits dysregulated lipid metabolism, driving tumor progression and therapeutic resistance. This review aims to elucidate the roles of fatty acid, sphingolipid, and cholesterol metabolism in HCC pathogenesis and explore emerging therapeutic strategies targeting these pathways. Key findings demonstrate that upregulated enzymes like fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), enhance de novo lipogenesis and β-oxidation, and promote HCC proliferation, invasion, and apoptosis evasion. Sphingolipids exert dual functions: ceramides suppress tumors, while sphingosine-1-phosphate (S1P) drives oncogenic signaling. Aberrant cholesterol metabolism, mediated by HMG-CoA reductase (HMGCR), liver X receptor α (LXRα), and sterol regulatory element-binding protein 1 (SREBP1), contributes to immunosuppression and drug resistance. Notably, inducing ferroptosis by disrupting lipid homeostasis represents a promising approach. Pharmacological inhibition of key nodes-such as FASN (Orlistat, TVB-3664), sphingomyelin synthase (D609), or cholesterol synthesis (statins, Genkwadaphnin)-synergizes with sorafenib/lenvatinib and overcomes resistance. We conclude that targeting lipid metabolic reprogramming, alone or combined with conventional therapies, offers significant potential for novel HCC treatment strategies. Future efforts should focus on overcoming metabolic plasticity and optimizing combinatorial regimens.

Keywords:  Hepatocellular carcinoma; cholesterol; fatty acid; lipid metabolism; sphingolipids

DOI:  https://doi.org/10.32604/or.2025.066440
Nat Commun. 2025 Nov 03. 16(1): 9690

Targeting cancer glutamine dependency with a first-in-class inhibitor of the mitochondrial glutamine transporter SLC1A5_var.

Yulseung Sung, Ya Chun Yu, Mirim Lee, Seonghun Lim, Yechan Lee, Mincheol Kang, Doru Kwon, Apeksha Parajulee, Junjeong Choi, Do Sik Min, Kuglae Kim, Wan Namkung, Yun-Hee Kim, Sang Myung Woo, Nam Doo Kim, Hee Chan Yoo, Jung Min Han.

The mitochondrial glutamine transporter SLC1A5_var plays a central role in the metabolic reprogramming of cancer cells by facilitating glutamine import into mitochondria for energy production and redox homeostasis. Despite its critical function, the development of effective and selective inhibitors targeting SLC1A5_var has remained a significant challenge. Here, we introduce iMQT_020, a selective allosteric inhibitor identified through structure-based screening. iMQT_020 disrupts the trimeric assembly of SLC1A5_var, causing metabolic crisis in cancer cells and selectively suppressing their growth. Mechanistically, iMQT_020 reduces glutamine anaplerosis and oxidative phosphorylation, resulting in a broad disruption of cancer metabolism. Additionally, iMQT_020 treatment epigenetically upregulates PD-L1 expression, enhancing the efficacy of combination therapies with anti-PD-L1 immune checkpoint inhibitors. These findings highlight the therapeutic potential of targeting SLC1A5_var as a critical metabolic vulnerability in cancer and demonstrate that targeting allosteric interprotomer interactions is a novel and promising therapeutic strategy for cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-64730-2
Adv Sci (Weinh). 2025 Nov 07. e11947

CypA Mediates Non-Small Cell Lung Cancer Chemoresistance by Attenuating Ferroptosis via Stabilizing SLC7A11.

Zhongcheng Wang, An Li, Ziwei Song, Xiangming Liu, Yong Ge, Zhiqiao Chen, Yuhui Liu, Boyu Zhang, Hao Zhang, Ting Lan.

  Non-small cell lung cancer (NSCLC) remains a major oncological challenge due to intrinsic or acquired chemoresistance, underscoring the urgent need to decipher novel regulatory mechanisms. Here, cyclophilin A (CypA) is identified as a critical mediator of cisplatin (DDP)/paclitaxel (DTX) resistance in NSCLC by suppressing ferroptosis, an iron-dependent form of regulated cell death. CypA is significantly overexpressed in DDP/DTX-resistant NSCLC cell lines and patient tissues, correlating with poor prognosis. Mechanistically, CypA stabilizes the ferroptosis suppressor SLC7A11 by competitively binding to its K37 site, blocking ubiquitination and proteasomal degradation mediated by the E3 ligase TRIM3. This interaction maintains cystine uptake, glutathione biosynthesis, and redox homeostasis, thereby attenuating lipid peroxidation and ferroptosis induction by chemotherapeutics. knockout of CypA or pharmacological inhibition with cyclosporine A (CsA) reverse resistant NSCLC cells to DDP/DTX both in vitro and in vivo by restoring ferroptosis. Combined CsA and chemotherapy treatment significantly enhances tumor regression, as evidenced by increased 4-HNE and reduced SLC7A11 expression in vivo. The study uncovers a CypA/SLC7A11/TRIM3 axis governing ferroptosis evasion in NSCLC chemoresistance and highlights CypA as a promising therapeutic target. Repurposing CsA to inhibit CypA represents a translatable strategy to overcome chemotherapy resistance, offering preclinical validation for improving outcomes in NSCLC patients.

Keywords:  CypA; SLC7A11; chemoresistance; ferroptosis; non‐small cell lung cancer

DOI:  https://doi.org/10.1002/advs.202511947
Oncol Res. 2025 ;33(11): 3327-3346

Lactylation in Cancer: Unlocking the Key to Drug Resistance and Therapeutic Breakthroughs.

Xiangnan Feng, Dayong Li, Pingyu Wang, Xinyu Li, Guangyao Li.

  Lactylation, a post-translational modification process that adds lactate groups to lysine residues, plays a crucial role in cancer biology, especially in drug resistance. However, the specific molecular mechanisms of lactylation in cancer progression and drug resistance are still unclear, and therapeutic strategies targeting the lactylation pathway are expected to overcome metabolic reprogramming and immune evasion. Therefore, this article provides a comprehensive description and summary of lactylation modification and tumor drug resistance. Numerous studies have shown that, due to the Warburg effect, there is an abnormally high level of lactate in tumor cells. Elevated levels of lactate promote metabolic reprogramming and alter key cellular processes, including gene expression, DNA repair, and immune regulation. These cellular processes are precisely the key factors for tumor cells to develop drug resistance. Lactylation also affects the tumor microenvironment, promoting immune evasion and resistance to immunotherapy in tumor cells. This modification affects proteins involved in metabolic pathways, glycolysis, and mitochondrial function, further supporting tumor growth and metastasis. Therefore, this article provides a comprehensive description and summary of lactylation modification and tumor drug resistance to clarify the specific mechanisms between the two and provide references and directions for future research on tumor drug resistance.

Keywords:  Lactylation; cancer metabolism; drug resistance; immune evasion; tumor microenvironment

DOI:  https://doi.org/10.32604/or.2025.067343
Drug Resist Updat. 2025 Nov 04. pii: S1368-7646(25)00126-8. [Epub ahead of print]84 101323

Nanoparticles-mediated mitochondrial relocation of lipid-lowering drugs shape energy metabolism to conquer acquired immune resistance.

Cheng Li, Wei Xiong, Jiahao Liu, Ke Li, Haoxiang Wang, Zhengxiang Wang, Feiyu Liu, Jianliang Shen, Zaigang Zhou, Shenpeng Ying, Long Wang.

  CD276, is a fatal recently discovered immune checkpoint proteins of B7 family. Due to the not clearly uncovered signal pathways that involved in the expression of CD276 in tumors, few strategies were discovered to regulate CD276. Here, we newly discovered that abnormal tumor mitochondrial activation played a vital important role in raising CD276 expression through targeting AMPK/mTOR signal pathway. Then, it was also revealed that clinical usable lipid-lowering drugs with mitochondria oxidative phosphorylation (OXPHOS) and glycolysis inhibiting capacity, like fenofibric acid (FFA), exhibited desired programmed death ligand-1 (PD-L1) and CD276 co-suppression capacity. To better deliver FFA to tumor mitochondria, IR-FFA was synthesized by linking the mitochondria-targeting heptamethylene cyanine IR-68 with FFA, followed by self-assembly with albumin (Alb) to create IR-FFA@Alb nanoparticles. By doing so, the dosage needed for IR-FFA@Alb to depress CD276 and PD-L1 expression was 100 times lower than free FFA. Then, IR-FFA@Alb monotherapy effectively inhibited tumor growth both in vitro and in vivo. Moreover, the combination therapy of IR-FFA@Alb nanoparticles and radiotherapy (RT) effectively avoid the frequently occurred immune tolerance phenomenon of RT by co-depression CD276 and PD-L1. These results altogether showed the possibility of using lipid-lowering drugs as multi-functional immune checkpoint inhibitors to sensitize tumor therapy.

Keywords:  CD276; Mitochondrial Targeting; Nanoparticles; Programmed death ligand-1; Radiotherapy

DOI:  https://doi.org/10.1016/j.drup.2025.101323
Cell Death Dis. 2025 Nov 04. 16(1): 792

A novel strategy to target metabolic dependencies in acute myeloid leukemia.

Nithya Balasundaram, Hamenth Kumar Palani, Arvind Venkatraman, Yolanda Augustin, Shruthi Pichandi, Clement Regnault, Majeela Solomon, Abirami Rajasekaran, Mohammed Yasar, Swathy Palani Kumar, Reeshma Nair Radhakrishnan, Anu Korula, Uday Prakash Kulkarni, Eunice Sindhuvi Edison, Poonkuzhali Balasubramanian, Biju George, Aby Abraham, Sanjeev Krishna, Vikram Mathews.

Acute myeloid leukemia (AML) remains difficult to cure despite recent advances. Off-target side effects of drugs currently used lead to significant morbidity and mortality. There is recognition that in AML, there is an increased dependence on OXPHOS metabolism, especially in the leukemia stem cell compartment (AML-LSC). It is also recognized that there is potential to exploit this vulnerability to treat AML. Drug re-purposing screens have suggested the potential use of artesunate (ART) to inhibit mitochondrial respiration. We have explored the potential role of ART as an additive agent in treating AML in combination with conventional therapy. Through in-vitro and in-vivo mouse model studies, we demonstrate the mechanism and efficacy of these combinations and their potential to overcome venetoclax resistance. We further demonstrate the specificity of these combinations with minimal off-target effects on normal hematopoietic stem cells (HSC). These observations warrant exploration of the additive role of ART in clinical trials.

DOI: https://doi.org/10.1038/s41419-025-08129-3
Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2409556122

Restoration of cGAS in cancer cells promotes antitumor immunity via transfer of cancer cell-generated cGAMP.

Alexander M Cryer, Pere Dosta, Michelle Z Dion, Leonardo de la Parra Soto, Eliz Amar-Lewis, Gabriela Garcia de Leon Carmona, Alejandro Abraham Espinosa Pérez, Diego Fernando Ruiz Aguilar, Triana Huerta, Beatriz Nicolás Ruiz, Nathalie Nicole Casteele Hernandez, Yael Soria, Natalie Artzi.

  Cancer cells comprise a significant proportion of the tumor microenvironment (TME) and often have compromised expression or repression of cyclic GMP-AMP (cGAMP) synthase (cGAS), which prevents effective stimulation of interferon genes (STING) signaling. Here, we leverage the cancer cells and hijack their cellular machinery for increased production of cGAMP, differing from conventional strategies whereby synthetic STING agonists are delivered to immune cells in the TME as a bolus dose, are rapidly cleared and can cause systemic toxicity. Increasing evidence suggests that cGAMP derived from cancer cells can act on proximal immune cells, activating STING, contributing to an antitumor immune response. We used lipid nanoparticles (LNPs) to deliver mRNA coding for cGAS which catalyzes the production of cGAMP. We observed dramatic increases in extracellular and intracellular cGAMP when cancer cells were transfected with cGAS mRNA and genomic DNA, the substrate for cGAS. We confirmed that cGAS and cGAMP are functional due to activation of immune cells, through a combination of extracellular transfer and cell-cell contact mechanisms. Treatment of syngeneic murine melanoma with cGAS LNPs reduced tumor growth significantly and further benefit was observed upon combination with immune checkpoint blockade (anti-PD-1). Moreover, we found increased activation in CD8+ T cells, NK cells, macrophages, and dendritic cells in the TME post treatment with cGAS LNPs. These findings highlight how cancer cells can be used to actively contribute to their own elimination and may be a broadly applicable strategy for delivery of other reprogramming molecules to cancer cells and wider therapeutic combinations.

Keywords:  cGAS–STING; cancer; cell–cell communication; delivery; mRNA

DOI:  https://doi.org/10.1073/pnas.2409556122
Cancer Res Treat. 2025 Nov 03.

PHF10 is a Novel Substrate of Keap1 to Protect Non-Small-Cell Lung Cancer (NSCLC) Cells Against Oxidative Stress and Confer Ferroptosis Resistance.

Xuan Lu, Ningning Kang, Yajun Chen, Xinru Zhao, Donglin Zhu, Jun Yang, Yong Yang, Hongya Xie.

   Purpose: Keap1 mutations mainly caused NRF2-dependent anti-oxidative stress responses, yet whether there are other downstream substrates and pathways remains unknown. This study aimed to uncover the role of Keap1 mutations in regulating PHF10-NRF2 axis in NSCLC and ferroptosis evasion.
Materials and Methods: Tandem affinity purification with mass spectrometry was used to screen peptides. Co-IP and ubiquitination assays were used to confirm the Keap1-PHF10 axis. A series of analyses in cell lines, patient samples, and xenograft models were conducted to uncover the functional dependency between Keap1 and NRF2. Transmission electron microscope was used to detect mitochondrion swelling under ferroptosis.
Results: Here, we reported that Keap1 binds and promotes polyubiquitination and degradation of PHF10, a subunit of the PBAF complex. NSCLC-associated Keap1 mutations are incapable of degrading PHF10, and thus induces PHF10 proteins stability. PHF10 ablation shows synthetic lethality in Keap1-deficient NSCLC cells. Mechanistically, PHF10 interacts with NRF2 to activate its downstream targets and enhance the NRF2-dependent anti-oxidative stress capacity in NSCLC. PHF10 recruits SMARCA2, one core cBAF subunit, to increase chromatin accessibility in NRF2-binding transcriptional regions. Cancer-associated Keap1 mutants confer resistance to ROS-induced cell death via accumulating PHF10-SMARCA2 complex. Increased PHF10 further induced ferroptosis resistance in Keap1-deficient NSCLC. Lastly, we utilized one small molecule inhibitor, SMARCA2-IN-8, to inhibit progression of Keap1-deficient NSCLC murine models.
Conclusion: Together, our study highlight the synthetic lethal relationship between Keap1 and PHF10, and provide targeting PHF10-SMARCA2 complex as an effective option to hit Keap1-deficient NSCLC.

Keywords:  Ferroptosis; Keap1; Lung neoplasms; NRF2; PHF10; Ubiquitination

DOI:  https://doi.org/10.4143/crt.2025.635
Adv Sci (Weinh). 2025 Nov 06. e11744

Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver.

Wensi Zhao, Lei Zhao, Yannan Lian, Zhiwei Liu, Yaqi Li, Xuege Wang, Mingya Zhang, Ni Li, Jingli Guo, Danqing Shen, Shaobo Mo, Jiahao Li, Linhui Zhai, Jiahui Ni, Sangkyu Lee, Bin Liu, Jing Li, Fei Wang, Junjie Peng, Jun Qin, Minjia Tan.

  Colorectal liver metastasis (CRLM) is one of the leading death causes among colorectal cancer (CRC) patients, yet its underlying molecular events remain poorly understood, particularly at the proteomic and phosphoproteomic levels. A proteogenomic analysis combining genomics, transcriptomics, proteomics, and phosphoproteomics is performed on 102 samples from 34 treatment-naïve CRLM patients, including primary CRC, adjacent normal colorectal, and matched liver metastasis tissues. CRC cell lines, organoids, mouse models, and an independent patient cohort are used to validate the findings. Proteomics and phosphoproteomics show profoundly dysregulated pathways in liver metastasis tissues, notably disruptions in carbon metabolism. Functional validation using CRC organoids and mouse models demonstrates that the one-carbon metabolism enzyme SHMT1 promotes CRC tumorigenesis and metastasis via formate-mediated AMPK inhibition, whereas PIM kinase-dependent NDRG1 Ser330 phosphorylation exacerbates liver metastasis by promoting ubiquitin-dependent degradation of NDRG1. Unsupervised clustering identifies two proteomic subtypes of liver metastasis samples with distinct clinical outcomes: a poor-prognosis C1 (metabolism) subtype and a better-prognosis C2 (RNA function) subtype. Considering expression frequency, specificity, and functional relevance, FTCD, GPD1, SOD2, and EIF4B Ser422 phosphorylation are further identified and validated as subtype prognostic biomarkers. This study provides critical insights into the molecular mechanisms underlying CRLM and offers resources for high-risk metastatic CRC.

Keywords:  SHMT1; biomarker; colorectal liver metastasis; phosphoproteomics; proteomic subtype; proteomics

DOI:  https://doi.org/10.1002/advs.202511744