Precision medicine has evolved through distinct phases, from the origins of the Human Genome Project to mutation-based targeted therapies. This editorial posits that “stereological cell biomedicine” could be a new approach promoting the development of the next generation of precision medicine. This emerging discipline transitions the focus from genomic data to the multi-dimensional and spatiotemporal complexity of single cells. Driven by advances in Stereo single-cell multi-omics (Stereo Cell-seq), spatial transcriptomics (Stereo-seq), and single-cell surfaceomics (sc-surfaceome), this approach aims to capture the stereologically dynamic interactions between organelles within a cell and between cells in the tissue. We argue that understanding the spatiotemporal location of molecules, particularly protein interactions at organelle interfaces and on the cell surface, is as critical as their abundance for defining cellular function in health and disease. Integrating these high-resolution measurements with artificial intelligence and computational modelling will bridge the gap between advanced omics and pathology. Initiatives such as the newly established European Stereo Cell Center (ESCC) signal a global shift towards this new paradigm, which promises to unlock novel diagnostic biomarkers and therapeutic targets for truly multi-factorial and dynamic precision medicine.
Although the contribution of matrix stiffness to aggravating the malignant features of HCC cells has been well documented, the effects of matrix stiffness on chemoradiotherapy resistance and its underlying mechanism remain largely elusive.
To delineate the role of matrix stiffness in HCC progression, we engineered novel in vivo animal models with defined liver stiffness and a complementary tunable hydrogel culture system. This integrated approach enabled a comprehensive investigation into how biomechanical cues modulate HCC cell proliferation and DNA repair both in vitro and in vivo.
High stiffness stimulation noticeably enhanced cell proliferation and cell survival from DNA damage through changing the expression and distribution of metabolic enzyme PFKFB3. Specifically, high stiffness stimulation prominently suppressed PFKFB3 ubiquitination by downregulating E3 ubiquitin ligase NEDD4, and then increased the stability of PFKFB3 protein to enhance glycolysis, ultimately promoted HCC growth. Meanwhile, high matrix stiffness stimulation also effectively strengthened the DNA damage repair ability of irradiated HCC cells, and PFKFB3 nuclear translocation mediated in matrix stiffness-regulated DNA damage repair by interacting with Ku70.
Our results delineate a PFKFB3-mediated pathway that underpins how increased matrix stiffness potentiates HCC growth and compromises radiotherapy efficacy. These findings not only highlight the contribution of matrix stiffness to tumor growth and DNA damage repair in HCC, but also disclose a previously unidentified nonmetabolic function of PFKFB3.
The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon (IFN) genes (STING) pathway emerges as a dual-functional role in urologic malignancies, exhibiting context-dependent tumor-suppressive and pro-tumorigenic activities. When this pathway is activated in urologic tumors, IFN transcription and CD8+ T cell infiltration are triggered, which has an anticancer effect. However, this pathway facilitates the development of prostate cancer through the up-regulation of regulatory B cells. STING palmitoylation triggers immune escape in renal cell carcinoma, and the STING/SLC14A1 axis also mediates chemoresistance in bladder cancer.
Based on these findings, we establish the first systematic comparison of tissue-specific STING regulation in urological malignancies, challenging the conventional tumor suppressor-centric view. This review also highlights several innovative strategies leveraging this duality during urologic cancers. The demand for the long-term safety and effectiveness of these targeted STING treatments has not been fully met.
This study introduces a framework that harnesses the dual functions of the cGAS-STING pathway to strengthen immunotherapy approaches and improve clinical outcomes to bridge the pre-clinical-clinical gap.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder caused by AGXT mutations, leading to hepatic oxalate overproduction, nephrolithiasis, and progressive renal failure. This study aims to evaluate the therapeutic potential of base editors delivered via lipid nanoparticles (LNPs) for treating PH1.
We utilized LNPs to deliver the base editor variant spG-ABE8e into a PH1 rat model. A single-dose injection of LNP-ABE was administered to assess its efficacy in correcting the pathogenic Agxt point mutation.
Treatment with LNP-ABE achieved highly efficient correction of the Agxt mutation, which resulted in the normalization of urinary oxalate excretion, prevention of calcium oxalate deposits, and reversal of renal injury-associated gene expression profiles in PH1 rats. Furthermore, this study identified the minimum Agxt correction efficiency required for urinary oxalate normalization.
Our findings demonstrate that LNP-mediated delivery of base editors can effectively correct AGXT pathogenic mutations and ameliorate disease phenotypes in PH1, providing critical preclinical benchmarks for future clinical translation.
The base editor precisely corrected the Agxt gene with high efficiency in PH1 rats.
LNP-delivered Adenine Base Editor (ABE) normalized urinary oxalate levels and prevented calculus formation.
This study identified the minimal Agxt correction efficiency required for urinary oxalate normalization.
The immune microenvironment of the three most common gynaecological malignancies—tubo-ovarian cancer, endometrial cancer and cervical cancer—has not been systematically studied, limiting clinical application.
This study analyses 272 389 CD45+ immune cells by integrating publicly available single-cell RNA sequencing (scRNA-seq) data from 111 tumour and non-malignant tissue samples. We identified distinct subsets within immune cells: 11 for monocytes/macrophages, six for CD4 T cells, eight for CD8 T cells and five for B cells, detailing their distribution, prevalence and distinct functions.
A pro-angiogenic macrophage subset linked to NF-κB signalling was associated with worse clinical outcomes and an interferon-primed macrophage subset correlated with improved survival by recruiting T cells through CXCL9/10/11 secretion, as confirmed by multi-colour immunohistochemistry. T cells exhibited dynamic roles in tubo-ovarian cancer, with CD8 Tex cells contributing to immune dysfunction and poor prognosis, while CD8 Trm cells in early-stage tumours supported immune surveillance. Additionally, we identified co-stimulatory and co-inhibitory receptor interactions and classified distinct B cell subsets with varying prognostic implications.
This comprehensive analysis of the tumour immune microenvironment in gynaecological malignancies provides new insights into immune cell composition and function offering potential for optimising immunotherapies and improving clinical outcomes in these cancers.
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