Research Spectrum: Biomedical Research & Applications

Nuclear PD-L1: an emerging oncogenic driver and promising therapeutic target in cancer

Citing Guo — 2026-08-20

Programmed cell death-ligand 1 (PD-L1) is best known as a membrane immune checkpoint; however, accumulating evidence indicates that PD-L1 can also localize to the nucleus, where it may exert PD-1-independent, cell-intrinsic functions in cancer. Emerging studies associate nuclear PD-L1 (nPD-L1) with aggressive disease, therapeutic resist-ance, and poor outcomes across multiple malignancies. In this review, we summarize current evidence regarding the regulatory mechanisms that may govern PD-L1 nuclear translocation, including post-translational modifica-tions, stress-responsive signaling, and importin-dependent trafficking. We further discuss how nPD-L1 has been linked to adaptive programs involving DNA damage repair, metabolic rewiring, transcriptional regulation, and tumor microenvironment remodeling in context-dependent models. Clinically, nPD-L1 has potential relevance as a prog-nostic biomarker and as a candidate indicator of resistance to immunotherapy, radiotherapy, and chemotherapy, although prospective validation remains limited. We also highlight current challenges in detection and quantification, including the need for standardized multiplex imaging and digital pathology approaches. Finally, we discuss emerg-ing therapeutic strategies aimed at disrupting PD-L1 nuclear trafficking or selectively targeting nuclear PD-L1-asso-ciated functions. Collectively, these findings support nPD-L1 as an important and potentially actionable dimension of PD-L1 biology that warrants further mechanistic and translational investigation.

Many but not all pathogen-associated molecular patterns aggravate neurogenic heterotopic ossification after spinal cord injury

Selwin G. Samuel — 2026-08-20

Background: Neurogenic heterotopic ossifications (NHOs) are heterotopic bones that develop in periarticular muscles after traumatic brain (TBI) and spinal cord injuries (SCI). The mechanisms leading to NHO are incompletely understood and the only effective treatment to-date remains surgical resection. We previously established that several inflammatory pathways drive NHO pathogenesis in injured muscles in a mouse model of NHO and in humans. We also demonstrated a functional association between gram-negative bacterial infections and NHO development via lipopolysaccharide (LPS), a pathogen associated molecular pattern (PAMP), which exacerbated NHO in a Toll-like receptor-4 (TLR4)-dependent manner in mice.
Methods: Using our mouse model of NHO induced by SCI and muscle injury in mice, we tested the effect of a large array of purified PAMPs post-surgery to mimic fungal, viral and bacterial infections and measured NHO bone volumes by micro-computerized tomography (microCT). The effect of PAMPs was also tested in vitro on human muscle progenitors and monocyte/macrophage populations.
Results: Muscle progenitors and monocyte/macrophage populations from humans and mice express numerous pattern recognition receptors. In mice, numerous PAMPs produced by bacteria, viruses and fungi exacerbated NHO formation, and the majority of these PAMPs indirectly stimulated fibro-adipogenic progenitor (FAP) calcium mineralization in vitro via macrophages. Likewise, in humans, some PAMPs, particularly those binding to TLR2, directly and indirectly increased the calcium mineralization and osteogenic differentiation of human FAPs isolated from muscles surrounding human NHO. Finally, we established that the indirect stimulation of human FAP mineralization was mediated by inflammatory cytokines IL-1 and oncostatin M secreted by monocytes in response to PAMPs. Overall, our findings suggest that numerous types of infection have the potential to exacerbate NHO development and further highlight the role of oncostatin M and IL-1 signaling pathways in NHO pathophysiology.

Protein arginine methyltransferases in cancer: mechanisms, functions, and therapeutic opportunities

Yoonae Jeong — 2026-05-21

Protein arginine methyltransferases (PRMTs) catalyze the methylation of arginine residues on both histone and non-histone substrates, orchestrating cellular processes such as transcriptional regulation, RNA splicing, signal transduction, and DNA damage response. Because dysregulated methylation reprograms epigenetic and post-transcriptional landscapes to promote malignant transformation, aberrant PRMT activity is closely associated with tumorigenesis and cancer progression. Major family members, containing PRMT1, CARM1, PRMT5, and PRMT6, regulate gene expression through site-specific histone methylation, thereby contributing to the transcriptional activation or repression. PRMTs also methylate a wide range of non-histone proteins, including transcription factors, splicing regulators, and signaling intermediates, to coordinate cell cycle progression, DNA repair, and RNA metabolism. Collectively, PRMT-mediated methylation contributes to higher-order cancer phenotypes, including metabolic reprogramming― through modulation of glycolytic flux, lipid biosynthesis, and redox homeostasis―and immune evasion via altered immune signaling and checkpoint pathways within the tumor microenvironment. Recent advances in chemical biology have led to the development of selective PRMT inhibitors, several of which are currently under clinical evaluation. In this review, we provide a comprehensive and integrative overview of PRMT biology, systematically organizing current knowledge from multilayered regulatory mechanisms to downstream oncogenic effects and emerging therapeutic opportunities.

Structure, mechanism and clinical relevance of NRG1 fusions in cancer

Clarisse Thiollier‑Schmitt — 2026-08-20

NRG1 gene fusions have been identified in patients with various solid tumors. Such patients have aggressive tumors and respond poorly to currently available treatments. There are many gene partners described for NRG1 fusions, and the structures and roles of the chimeric proteins are not always correctly understood. Here, we gather information on 665 reported patients with a total of 115 different known gene partners, and discuss structural elements supposed to play important roles in the biology of NRG1 fusions in cancer. This gives a better understanding of the biology of NRG1 fusions, and will help in the development of new therapeutic approaches. Our methodology described in this review can also be used for the study of other genes with disease-related fusions.

Antifungal resistance: from classical mechanisms to the expanding role of acetyltransferases

Silvia Maria Cordeiro Werneck — 2026-08-20

Antifungal resistance represents a growing global health challenge, driven by limited therapeutic options, inadequate use of both clinical and environmental drugs, and the remarkable adaptive capacity of fungal pathogens. While resistance has classically been attributed to genetic alterations affecting drug targets and efflux systems, accumulating evidence indicates that regulatory mechanisms play a critical role in shaping antifungal susceptibility. This review highlights that acetyltransferases constitute important and active components of antifungal resistance, operating through multiple integrated mechanisms. Notably, recent studies have extended this framework by identifying the direct enzymatic inactivation of antifungal agents by acetyltransferases, which emerges as an additional resistance mechanism and establishes a functional parallel with antibiotic acetylation in bacteria. These findings highlight acetyltransferases as clinically relevant drivers of antifungal resistance and suggest that targeting these enzymes may enhance the efficacy of existing antifungal therapies and reduce treatment failure.