bims-metorg 2026-01-25 papers

Issue of 2026–01–25
five papers selected by
Bruna Martins Garcia, CABIMER

Cancer Res. 2026 Jan 22.

ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.

Shanchun Chen, Chao Chang, Xiaoqi Liu, Rui Wang, Yongcan Liu, Die Meng, Boxuan Wang, Yuhang Hai, Chaoqun Deng, Yanran Tong, Xiaojiang Cui, Siyang Wen, Guobing Yin, Manran Liu.

Solid tumors frequently preferentially metastasize to specific organs. Metabolites within metastatic niches have emerged as critical regulators of organotropic metastasis. Here, we found that palmitic acid (PA) accumulated in both pre- and macro-metastatic lung niches. Lung-preferential metastatic breast cancer (LM-BC) cells secreted exosomal USP47 that was taken up by lung-resident alveolar type II epithelial cells (AT2) and enhanced fatty acid synthesis via YAP activation, resulting in PA enrichment and subsequent lung metastasis. ACSL5 in LM-BC cells facilitated PA adaptation by inducing COX2-mediated PGE2 accumulation and subsequent activation of the PI3K/AKT and ERK signaling pathways through EP4, which promoted cell survival and lung metastasis. Moreover, ACSL5 boosted levels of palmitoyltransferases, further enhancing COX2 expression, which could be inhibited by the palmitoylation inhibitor 2-bromopalmitate (2-BP). Notably, the enrichment of PA, accumulation of PGE2, and activation of the ACSL5/COX2/EP4 axis in lung metastases of BC patients correlated with poorer clinical outcomes. Limiting PA intake or targeting the ACSL5/COX2/EP4 axis enhanced paclitaxel efficacy in a breast cancer mouse model. Collectively, these findings highlight the critical role of PA and ACSL5/COX2/EP4 signaling in lung metastasis, which can act as promising targets for enhancing the efficacy of chemotherapy in BC patients with lung metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0866

Adv Sci (Weinh). 2026 Jan 21. e73843

Cholesterol Promotes Lung Adenocarcinoma Brain Metastasis by Stabilizing EGFR Protein to Drive EMT, Metabolic Reprogramming, and Premetastatic Niche Formation.

Ying Chen, Xiaoteng Cui, Xinyi Shi, Xu Yang, Yujing Cao, Haolin Li, Qi Zhan, Qixue Wang, Ang Li, Qihong Cheng, Yunfei Wang, Junhu Zhou, MingJie Wang, Chunsheng Kang, Xiaomin Liu.

Brain metastasis is a major cause of mortality in advanced lung adenocarcinoma (LUAD). Accumulating evidence indicates that dysregulated lipid metabolism contributes to metastatic colonization; however, how cholesterol functions as a downstream effector within established lipid-metabolic programs to regulate key steps of the LUAD brain metastasis (LUAD-BM) cascade remains incompletely defined. Here, we demonstrate that cholesterol directly engages EGFR and stabilizes its membrane localization by blocking ubiquitin-proteasome-mediated degradation, thereby sustaining AKT/NF-κB signaling. This signaling axis promotes glycolytic reprogramming and epithelial-mesenchymal transition in LUAD cells, enhancing metastatic capacity and resistance to TKIs. Cholesterol also disrupts blood-brain barrier integrity by reducing endothelial membrane fluidity and accelerating Claudin-5 ubiquitination and degradation. Within the brain microenvironment, cholesterol directly interacts with IL-4Rα, facilitating its recruitment into lipid rafts and activation of JAK1/STAT6 signaling, which drives microglial M2 polarization and establishes a permissive pre-metastatic niche. The cholesterol-lowering drug atorvastatin reverses these tumor-intrinsic and microenvironmental effects and suppresses LUAD brain metastasis in vivo. Retrospective clinical analyses further show that hypercholesterolemia is associated with shortened survival in LUAD-BM patients, whereas statin use correlates with improved outcomes. These findings identify cholesterol as a functional mediator downstream of lipid-metabolic dysregulation and therapeutic target in LUAD-BM.

Keywords: EGFR; brain metastasis; cholesterol; glycolytic reprogramming; lung adenocarcinoma

DOI: https://doi.org/10.1002/advs.73843

Front Immunol. 2025 ;16 1742855

Metabolic reprogramming in the post-metastatic tumor microenvironment: multi-omics insights into determinants of immunotherapy response.

Mengxi Li, Tingting Wang, Zhenwang Zhang, Yuxi Dongye.

Metabolic reprogramming has emerged as a central determinant of immune modulation in the post-metastatic tumor immune microenvironment (TIME). Alterations in glycolysis and lactate accumulation, lipid metabolic rewiring, metal-dependent cell death pathways such as ferroptosis and cuproptosis, and the tryptophan-IDO1-kynurenine axis collectively contribute to an immunosuppressive niche that drives tumor progression and therapeutic resistance. These metabolic shifts are not isolated events but are intricately connected with immune-regulatory networks, profoundly influencing the efficacy of immunotherapy. Advances in multi-omics technologies-including metabolomics, proteomics, single-cell sequencing, and spatial omics-have provided unprecedented resolution to decode these complex interactions, enabling the identification of predictive biomarkers, delineation of metabolic-immune signatures, and discovery of therapeutic vulnerabilities. Integrating these multi-layered datasets has paved the way for precision medicine strategies that tailor immunotherapy to patient-specific metabolic and immune contexts. Therapeutically, combining metabolic inhibitors with immune checkpoint blockade, exploiting ferroptosis or cuproptosis to enhance tumor immunogenicity, or modulating amino acid metabolism to reverse immune tolerance are promising strategies to overcome resistance and expand patient benefit. Looking forward, the integration of multi-omics-guided biomarkers, AI-driven analytics, and advanced delivery systems such as nanoparticles and engineered exosomes will accelerate the translation of these insights into clinical practice. Decoding the metabolism-immunity crosstalk through multi-omics not only advances our understanding of metastatic cancer biology but also paves the way for next-generation personalized and adaptive therapies that promise to enhance immunotherapy efficacy, prolong survival, and improve the quality of life for patients with advanced cancers.

Keywords: immunotherapy resistance; metabolic reprogramming; multi-omics integration; precision oncology; tumor immune microenvironment

DOI: https://doi.org/10.3389/fimmu.2025.1742855

J Adv Res. 2026 Jan 18. pii: S2090-1232(26)00072-X. [Epub ahead of print]

Metabolic vulnerabilities in ovarian cancer decoding the nexus between nutrient adaptation and therapy resistance.

Xiaoyu Guo, Zongang Liu, Xiaoman Li, Bingzheng Zhou, Jingyi Chen.

BACKGROUND: Ovarian cancer (OC) is a leading cause of gynecologic cancer-related mortality, primarily due to frequent therapy resistance and disease recurrence. Growing evidence indicates that metabolic reprogramming serves as a critical adaptive mechanism, allowing cancer cells to survive therapeutic stress.
AIM OF REVIEW: This review aims to decode the interplay between nutrient adaptation and therapy resistance in OC. It examines how alterations in key metabolic pathways contribute to treatment resilience and disease progression, and explores the potential of targeting metabolic vulnerabilities to improve therapeutic outcomes.
KEY SCIENTIFIC CONCEPTS OF REVIEW: We discuss how OC cells utilize metabolic pathways-including glycolysis, OXPHOS, glutamine metabolism, and lipid utilization-to promote survival, DNA repair, and immune evasion. Metabolic plasticity enables shifts between nutrient sources, driving resistance to platinum-based agents, PARP inhibitors, and anti-angiogenic therapies. These adaptations vary across subtypes, such as high-grade serous and clear cell carcinomas, and are influenced by specific mutations. Targeting metabolic enzymes-such as GLS, CPT1, OXPHOS complexes, or NAD+ synthesis-offers a promising strategic direction. Metabolic profiling may allow stratification of OC patients and pave the way for precision medicine approaches to overcome treatment resistance.

Keywords: Glycolysis; Ovarian cancer; Oxidative phosphorylation (OXPHOS); Therapy resistance; Tumor microenvironment

DOI: https://doi.org/10.1016/j.jare.2026.01.047

Mol Cell Proteomics. 2026 Jan 19. pii: S1535-9476(26)00008-3. [Epub ahead of print] 101513

Multi-Omics Profiling Reveals Distinct Immunosuppression and Metabolic Dysregulation in Aggressive Subtypes of Thyroid Cancer.

Shanying Gui, Kate Huang, Jianling Qiang, Yunzhao Chen, Meifu Gan, Zhaochang Jiang, Jiazi Qian, Chenchen Yi, Yi Ding, Huihui Jiang, Fulong Zheng, Wanlin Lei, Lulu Jin, Xiaowei Zhang, Hezhi Fang, Maofeng Wang.

Thyroid cancer comprises a heterogeneous group of malignancies with distinct clinical outcomes and molecular features, including papillary thyroid carcinoma (PTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC). This study aimed to delineate the molecular and immune landscapes of these subtypes and identify potential biomarkers for the aggressive forms, ATC and PDTC. We assembled a well-annotated cohort of 120 formalin-fixed paraffin-embedded (FFPE) samples, including 35 ATC, 18 PDTC, 37 PTC cases, and 30 adjacent normal tissues (N) paired with PTC, collected over the past decade from multiple hospitals. To our knowledge, this represents the largest clinical ATC/PDTC cohort subjected to multi-omics profiling and the first comprehensive proteomic analysis of these aggressive thyroid cancers. Using 4D-DIA proteomics on 118 tumors (ATC 34, PDTC 18, PTC 36, and N 30), integrated with total RNA-seq on 69 samples (ATC 10, PDTC 5, PTC 31, and N 23), we revealed substantial molecular similarities between ATC and PDTC, both markedly distinct from PTC and adjacent normal tissues. ATC and PDTC exhibited significant enrichment in immune-related and metabolic pathways, with transcriptomic data indicating aggressive phenotypes and pronounced immunosuppression. Distinct immune landscapes of ATC and PDTC were revealed with neutrophil extracellular trap (NET) formation and M0 macrophage accumulation as key immunosuppressive mechanisms. Notably, Fc fragment of IgG receptor IIa (FCGR2A, or CD32) was identified as a promising biomarker for ATC, implicating a functional link between immune evasion and tumor aggressiveness. Our findings provide a comprehensive molecular and immunological characterization of thyroid cancer subtypes, offering novel insights into the pathogenesis of ATC and PDTC, and identifying potential targets for diagnosis and precision therapy.

Keywords: ATC; FCGR2A; Immune Suppression; PDTC; Thyroid Cancer

DOI: https://doi.org/10.1016/j.mcpro.2026.101513