bims-prolim 2025-08-10 papers

Issue of 2025–08–10
five papers selected by
Bruna Martins Garcia, CABIMER

Med Oncol. 2025 Aug 02. 42(9): 399

Histone lactylation: a new target for overcoming immune evasion and therapy resistance.

Fatemeh Ghadyani, Pouyan Zandi, Soudeh Ghafouri-Fard.

While metabolic reprogramming in cancer is well-documented, the epigenetic consequences of lactate accumulation-particularly histone lactylation-remain underexplored as a unifying mechanism driving immune evasion and therapy resistance. This review synthesizes emerging evidence that lactylation remodels the tumor microenvironment (TME) by polarizing macrophages, exhausting T cells, and stabilizing oncogenic transcripts. We highlight the dual roles of lactylation as both a metabolic sensor and a mediator of immunosuppression, underscoring its potential as a therapeutic target. Unresolved questions, such as context-dependent effects of specific lactylation sites (e.g., H3K18la and H3K9la) and the interplay with other post-translational modifications, are critically evaluated. We also propose strategies to exploit lactylation pathways for combination therapies.

Keywords: Cancer; Histone lactylation; Immune escape; Therapy resistance

DOI: https://doi.org/10.1007/s12032-025-02940-w

Discov Oncol. 2025 Aug 08. 16(1): 1507

Multi-omics insights into Palmitoylation-mediated brain network remodeling and glioblastoma risk.

Shasha Tan, Jinliang You, Huijun Wang, Long Zhao, Shun Li, Xiaoping Tang, Hongjun Liu.

Keywords: Brain network remodeling; Glioblastoma; Multi-omics; Neuroimaging endophenotypes; Palmitoylation; Protective mechanism

DOI: https://doi.org/10.1007/s12672-025-03369-3

Int J Biol Sci. 2025 ;21(10): 4529-4548

The glucose sensor NSUN2-m5C modification regulates tumor-immune glucose metabolism reprogramming to drive hepatocellular carcinoma evolution.

Jing He, Boqiang Liu, Weijun Zhao, Hao Shen, Yi Wang, Weiqi Li, Chenqi Jin, Yifan Wang, Xiujun Cai, Liang Shi.

Tumor heterogeneity and the dynamic evolution of tumor immune microenvironment (TIME) contribute to therapeutic resistance and poor clinical prognosis. To elucidate this mechanism, we first established a murine tumor evolution model (TEM) and systematically identified evolutionary core genes demonstrating progressive alterations during evolution. Subsequently, we developed a single-cell TEM through integrative analysis of hepatocellular carcinoma (HCC) clinical specimens (n=10) with external cohorts (n=11), enabling dynamic characterization of tumor-immune interactions during evolution, while addressing ethical challenges associated with obtaining tumor tissues from multiple stages in a single patient. Through TEMs analyses, we identified a contrasting glucose metabolism pattern between malignant cells and CD8+ T cells during tumor evolution. Mechanistically, glucose metabolic dominance triggers NSUN2 upregulation in tumor cells, where this functional RNA methyltransferase stabilizes key glycolytic transcripts (GLUT1, HK2, PFKM) through mRNA methylation. The NSUN2-mediated GLUT1 stabilization enhances the competitive advantage of tumor cells in glucose acquisition, creating a positive feedback loop that accelerates malignancy and exacerbates CD8+ T cell dysfunction. Building on these insights, we designed a dual-targeting strategy combining GLUT1/NSUN2 axis inhibitor WZB117 with PD-L1 blockade, which synergistically suppressed tumor evolution and reversed immunosuppression in preclinical models, suggesting a novel synergistic therapeutic strategy for treatment-resistant HCC.

Keywords: 5-methylcytosine modification; metabolic reprogramming; single-cell sequencing; tumor evolution; tumor immune microenvironment

DOI: https://doi.org/10.7150/ijbs.115610

bioRxiv. 2025 Jul 26. pii: 2025.07.22.666143. [Epub ahead of print]

Glucose Metabolism Sustains Aberrant STAT3 Signaling in Colorectal Cancer via Glycosylated Paracrine Factors.

Kathryn Buscher, Kelsey Temprine, Christopher Mays, Noora Aabed, Samuel Kerk, Hannah N Bell, Joseph A Nieto Carrion, Harrison Greenbaum, Varun Ponnusamy, Sadeesh K Ramakrishnan, Costas A Lyssiotis, Xiang Xue, Yatrik M Shah.

The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. While STAT3 is canonically activated by cytokines such as IL-6, this activation is typically transient due to negative feedback mechanisms. In CRC, however, STAT3 is aberrantly and persistently activated, promoting tumor cell proliferation and survival. Here, we demonstrate that glucose sustains STAT3 activation independent of cytokine availability. By manipulating glucose metabolism, we show that both glucose and its downstream metabolite, GlcNAc, are essential for maintaining STAT3 activation. Moreover, cells with high basal STAT3 activity produce glucose-dependent glycosylated proteins that can activate STAT3 in neighboring cells via paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that a combination of glycosylated proteins likely acts synergistically. In vivo, inhibition of glycolysis reduces STAT3 activation in tumors, and genetic deletion of STAT3 in subcutaneous tumor models significantly decreases tumor growth. Together, these findings uncover a novel mechanism by which glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.

DOI: https://doi.org/10.1101/2025.07.22.666143

Mol Cancer. 2025 Aug 04. 24(1): 211

Unraveling the glyco-immunity nexus in pancreatic cancer.

Christabelle Rajesh, Richard D Cummings, Prakash Radhakrishnan.

Keywords: Immune signaling; Pancreatic cancer; Therapies; Tumor glycosylation; Tumor microenvironment

DOI: https://doi.org/10.1186/s12943-025-02417-4