Clinical and translational discovery最新文献

T cells are central orchestrators of adaptive immunity and play important and complex roles in chronic inflammation, despite that their roles remain even paradoxical. The dysregulations of T cells occur in chronic diseases, such as inflammation and cancer, from being protectors to potent drivers of tissue pathology.^1-3 Of those, the pro-inflammatory tissue-resident memory (TRM) T cells accumulate within the tissue, perpetuating a cycle of inflammation. Subsets of TRM T cells, including those producing the highly inflammatory cytokine interleukin-17 (IL-17), are directly implicated in tissue damage, to form the ectopic lymphoid tissues, remodel the microenvironment, and amplify the local response in inflammation and cancer.^{4, 5} Reformed lymphoid alter local gradients of inflammatory mediators to trap and retain more lymphocytes and exacerbate the microenvironmental bioecology. The pre-activated TRM-like T cells harboured in lungs of smokers as the pre-existing state of a tissue can create an immune pressure that reprograms subsequent tumour evolution and response to therapy and profoundly influences disease progression.⁶

The deep understanding of TRM T-cell phenomes and bio-behaviours provides new insights for the identification of diagnostic biomarkers and therapeutic targets. The TRM T cells as a special type of memory T cells are categorised on basis of the locations (e.g., gut-TRM, lung-TRM, brain-TRM), cell surface antigens (e.g., CD8⁺ TRM, CD4⁺ TRM) or cell identity gene markers measured by single-cell RNA sequencing (scRNA-seq).^7-9 One of biological characteristics is their long-term residence in specific tissue to take an immediate action in the initiation of immune responses to invaded pathogens and reduction infectious spreads, faster than circulating memory T cells. Of those, CD8⁺ TRM T cells are the majority responsible for antiviral and anti-tumour immunity and can directly terminate infected cells and pathogen replication by releasing inflammatory mediators and enzymes. CD4⁺ TRM can support other immune cells (such as B cells for antibody production, macrophages for activation) and regulate local immune responses to infectious and autoimmune diseases by enhancing the synergistic effects of the immune networks. In addition, TRM T cells play critical roles in the tissue repair by controlling microenvironmental contents of inflammatory mediators and recognising abnormal cells such as infected cells or cancer cells to reduce the risk of tissue damage and maintain microenvironmental immune bioecology. The molecular processes of reservable immune memory in TRM T cells can provide a number of alternatives for vaccination and immunotherapy.

Recent redefinition of redefining T-cell behaviour in inflamed or tumour microenvironment are largely driven by high-resolution techniques such as scRN

Congenital heart disease (CHDs) pose a significant public health burden, impacting nearly 1% of newborns each year. This review focuses on the genetic aspects of CHDs, examining their prevalence, causes and the significant advancements in genetic technologies used for their diagnosis and management. We cover the wide range of CHDs, from minor septal defects to critical conditions like hypoplastic left heart syndrome, and underscore the complex interaction among genetic and environmental influences contributing to these defects. The review stresses the importance of understanding genetic inheritance patterns, especially in families with a history of CHDs, and the essential role of genetic counselling in evaluating familial risk and informing reproductive choices. We also explore the latest developments in genetic technologies, such as genome-wide association studies, single-nucleotide variations and copy number variants, which have greatly improved our ability to pinpoint genetic risk factors for CHDs. These genetic discoveries have important clinical applications, including their use in tailoring treatment plans and enhancing prenatal diagnosis. This review aims to elucidate the genetic architecture of CHDs by integrating findings from recent research, with the goal of enhancing the lives of those affected and their families.

In the evolving landscape of cancer immunotherapy, tertiary lymphoid structures (TLS) have rapidly transitioned from a histological curiosity to a central mediator of anti-tumour immunity.¹ A growing body of evidence, particularly within renal cell carcinoma (RCC), has established a strong association between the presence of dense, mature TLS in the tumour microenvironment (TME) and significant clinical benefit from immune checkpoint inhibitor (ICI) therapy. A recent meta-analysis provided high-level evidence for this, confirming that high TLS density correlates with superior objective response rates and prolonged progression-free survival across solid tumours, including RCC.² This consensus is not only reshaping our understanding of the TME but also charting new paths for therapeutic innovation.

The significance of TLS lies in their function as fully equipped, in situ immune factories. Groundbreaking work using spatial transcriptomics has beautifully elucidated that within the TLS of RCC, a complete B cell maturation process occurs — from B cell recruitment and germinal centre reactions to the generation of antibody-producing plasma cells.³ These locally produced IgG antibodies can directly bind to and mark tumour cells for apoptosis. This elegant mechanism provides a compelling explanation for why TLS signatures are a key immunogenomic determinant for ‘exceptional responders’ to combination immunotherapy in RCC.⁴

However, the clinical utility of TLS is not a simple binary question; its value is deeply rooted in its heterogeneity. First, location and maturity are paramount. Studies indicate that it is the intratumoral and mature (i.e. secondary follicle-like) TLS that are most strongly associated with favourable outcomes and ICI efficacy.⁵ Second, the value of TLS is highly context-dependent on the surrounding immune milieu. A pivotal study proposed a more refined paradigm: optimal response to PD-1 blockade in RCC requires the combination of high TLS density with a low abundance of tissue-resident exhausted CD8⁺ T cells.⁶ This suggests that even a potent ‘immune factory’ is of limited use if the effector T cells are already terminally dysfunctional. This complex interplay may explain paradoxical reports of TLS correlating with poor prognosis in some RCC cohorts.⁷

These deepening insights are paving the way for clinical translation and future therapeutic strategies. To overcome the challenges of invasive biopsies, developing non-invasive surrogates is critical. An important clinical study has linked the baseline level of circulating unswitched memory B cells with the presence of intratumoral TLS and improved survival in patients with RCC treated with nivolumab, presenting a promising avenue for a liquid biopsy approach.⁸ This

Heart failure (HF) remains a global health burden and a leading cause of death and disability. In Asia, HF prevalence is projected to reach 74.5 million by 2050, a 127.6% increase from 2025,¹ driven by rising cardiometabolic disease across the region. While current therapies target haemodynamic impairment and pathological neurohormonal hyperactivation, they offer limited benefit against progressive myocardial decline and cardiovascular mortality. Novel therapeutics are urgently needed to overcome challenges of poor tissue specificity, limited intracellular delivery and suboptimal pharmacokinetics.

MicroRNAs (miRNAs) are small non-coding RNAs, typically 20–24 nucleotides long, that regulate key post-transcriptional gene expression by binding to complementary sequences in messenger RNAs (mRNAs), leading to mRNA degradation or inhibition of translation. MiRNAs have recently emerged as promising biomarkers and potential therapeutic targets in HF. Their clinical translation, however, hinges on precise delivery to minimize off-target effects and enhancing biodistribution. In this context, Lu et al. recently reported a cardiac targeting peptide (CTP; 12-amino acid sequence APWHLSSQYSRT) conjugated to miR-106a (CTP–miR-106a), which reversed cardiac hypertrophy and dysfunction in an angiotensin II/isoproterenol-induced mouse model of HF.² This study builds on prior in vitro evidence demonstrating that CTP–miR-106a selectively attenuates phenylephrine- and angiotensin II-induced cardiomyocyte hypertrophy, with preferential uptake over the human embryonic kidney 293 cell line, cardiac fibroblasts and endothelial cells.³

Following intravenous administration of 10 mg/kg of the dual-reporter construct Cy5.5–CTP–miR-106a–Cy3, which is linked via a disulphide bond cleavable by endogenous reductases to release Cy5.5–CTP and miR-106a–Cy3, cardiac expression of miR-106a peaked at 30 min post-injection.² This was accompanied by tissue-level expression of the miR-106a–Cy3 reporter. The Cy5.5–CTP moiety was subsequently expelled from the myocardium within 3.5 h and cleared via hepatic and renal pathways. In contrast, miR-106a–Cy3 remained upregulated in cardiac tissue at 3.5 h, and elevated miR-106a mRNA levels persisted up to 7 days. Importantly, neither miR-106a–Cy3 nor miR-106a gene expression was detected in the liver, kidney or lung, suggesting cardiac-specific uptake. However, this observation contrasts with earlier studies by the same group, in which mice injected with 10 mg/kg of Cy5.5–CTP alone (without miR-106a moiety) exhibited robust and peak uptake in the liver and kidney as early as 15 min post-injection.⁴ This uptake paralleled the observations in the heart but declined more slowly, indicating delayed clearance.

Despite these findings, the precise mechanisms underlying CTP's cardiac specificity remain unclear. It i

Computational modeling and simulation are playing an increasingly important role in oncology, bridging biological research, data science and clinical practice to better understand cancer complexity and inform therapeutic development. This special issue presents recent advances in multiscale modeling, artificial intelligence-driven systems, digital twins, and in silico trials, illustrating the evolving potential of computational tools to support innovation from bench to bedside. Together, these contributions outline a future in which precision medicine, adaptive therapies and personalized diagnostics are guided by integrative and predictive modelling approaches.

Clinical single-cell biomedicine is an emerging disciplines within molecular medicine that brings more advanced alternatives for disease diagnoses and therapies. With the rapid development of biotechnologies such as Stereo-seq and Stereo-cell, it is now possible to explore the spatiotemporal and dynamical changes of intracellular element and organelle locations, distributions, and functional and morphological phenomes in stereological single cells at multiple layers and orientations. Stereological single cells (StereoCell) will provide the precise multidimensional information on molecular interactions, organelle communications, and signaling pathways, as well as on the interventions involving small molecule-, protein-, and cell-based therapies with targets. This is achieved by integrating morphological images, molecular multi-omics, and clinical phenomics. StereoCell is one of biotechnological breakthroughs and milestones during of clinical translation of single-cell measurements to pathology, biochemistry, hematology, and bioliquid tests. It is also a new approach to discover and develop new diagnostic biomarkers and therapeutic targets, and a new way to dynamically monitor the disease progression and therapeutic effects. Thus, we believe that SereoCell, detected by Stereo-seq and Stereo-cell, will provide new insights into human diseases and reforming clinical practices.

The complement system, classically defined by its three canonical activation pathways, that is, classical, lectin, and alternative has long been considered a liver-derived, plasma-resident immune surveillance system. These pathways converge at the cleavage of complement (C3) and C5, generating potent effectors, such as C3a, C3b, C5a, and C5b that orchestrate immune clearance via inflammation, opsonisation, and membrane attack complex (MAC) formation^{1, 2} (Figure 1a–c). However, emerging evidence over the past decade has radically reshaped this view. We now recognise a spectrum of non-canonical complement activation routes including intracellular complosome activity, proteolytic cleavage by thrombin, kallikrein, cathepsins, and redox-driven activation that integrate complement into broader immune, metabolic and stress response networks.^2-9

A recent study by Donado et al.¹⁰ introduced a novel addition to this expanding repertoire granzyme K (GZMK), a serine protease released by cytotoxic lymphocytes, as a direct initiator of complement activation. In contrast to thrombin, kallikrein, and cathepsin, which bypass early steps to directly cleave C3 and C5 intracellularly,^{3, 7, 9} GZMK uniquely cleaves C4 and C2 on the cell surface, generating the classical C3 convertase (C4b2a) and C5 convertase (C4b2a3b) independent of antibody–antigen complexes or MBL/Ficolin. This places GZMK mechanistically alongside C1r and C1s and MASPs but fundamentally distinct in origin and context cell-autonomous, lymphocyte-derived, and recognition-independent (Figure 2a–f). This discovery reframes complement as not just a fluid-phase sentinel but also a cellularly initiated effector system.

Granzymes, a conserved family of serine proteases (GZMA, GZMB, GZMK, GZMM, GZMH in humans), are best known for their role in perforin-mediated cytotoxicity by CD8⁺ T cells and natural killer (NK) cells.¹¹ Yet beyond cytolysis, granzymes increasingly appear as modulators of inflammation and tissue remodelling. GZMB, for instance, cleaves extracellular matrix proteins and promotes autoantigen formation in autoimmune diseases.^12-17 GZMA, GZMB, and GZMM are implicated in viral control and inflammation, often via extracellular routes.

Amongst them, GZMK stands out as a non-cytolytic effector with immunoregulatory and pro-inflammatory properties. It is expressed in γδ T cells, invariant natural killer T (NKT) cells, and CD56bright⁺ NK cells and is upregulated in aging and chronic immune activation replication.^18-20 Structurally homologous to trypsin and GZMA, GZMK contains a unique heparin-binding domain that enables its interaction with cell-surface heparan sulphate proteoglycans (HSPGs).^21-25 It cleaves substrates such as SET nuclear proto-oncogene (a nucleosome assembly protein (SET)