Clinical and translational discovery最新文献

Nasopharyngeal carcinoma (NPC) treatment failure is driven primarily by distant metastasis, and increasing evidence indicates that metastasis risk and clinical outcome are more closely linked to the tumour's immune architecture than to anatomical staging alone.^1-3 Although NPC is typically an “immune-hot” tumour, many tumours fail to form an effective antitumor immune microenvironment.⁴ When tertiary lymphoid structures (TLSs) are immature or insufficient, cooperation between B cells and T cells is impaired, plasma-cell generation is reduced, and systemic control of micrometastases is consequently lost; conversely, mature TLSs, representing coordinated humoral and cellular immunity, are usually associated with tumour control and better responses to PD-1 inhibitors.^{5, 6} Therefore, the integrity of local immune architecture is mechanistically consistent with the tendency for distant metastasis, providing a biological basis for risk stratification and individualized therapy beyond TNM staging.

In this context, the study by Hou et al. provides an important breakthrough.⁷ The researchers constructed a TLS-related five-gene RNA score to predict the risk of distant metastasis in NPC, used cross-cohort Pareto optimization to select five key genes—RANBP17, TRIM9, ITGAM, ELOVL2, and KCNJ10—and achieved good predictive performance in an independent validation cohort (AUC = 0.74). When this score was integrated with clinical indicators (EBV DNA, BMI, TNM stage), the nomogram AUC increased to 0.90, outperforming clinical models alone (Figure 1). The researchers also found that high-risk patients showed downregulation of B-cell and Th17 pathways, restricted plasma-cell differentiation, and impaired TLS maturation, suggesting that disruption of the local humoral immune architecture is a key biological basis for distant metastasis in NPC and providing a reasonable mechanism for the phenomenon of being “immune-hot yet prone to metastasis.”

This study bridges tumour immunobiology to clinical practice, aligning risk prediction more closely with the biological reality of the immune landscape. However, beyond solving the question of “whether risk can be predicted,” the more important implication is “whether it can guide therapeutic intervention.” The true value of the TLS-RNA model lies in whether it can guide individualized therapy and immunologic decision-making. As the authors noted, the score can be assessed before first-line treatment to assist treatment selection.⁷ On this basis, we offer the following suggestions to deepen the research: For example, a clinical translation pathway from prediction to decision could be established. The TLS-RNA model could be used in prospective stratification trials to test whether patients with TLS-deficient, immune-cold tumours benefit from adding immunotherapy to chemoradiotherapy, while those

CD70, a tightly regulated immune co-stimulatory ligand under physiological conditions, becomes aberrantly and persistently overexpressed in a wide spectrum of malignancies, including renal cell carcinoma (RCC), glioblastoma and acute myeloid leukaemia. This tumour-restricted expression pattern, coupled with its potent immunomodulatory effects, positions CD70 as a uniquely actionable target in modern oncology. Unlike classical immune checkpoints, CD70 contributes to immune escape by chronically engaging CD27, leading to T cell exhaustion, regulatory T cell (Treg) expansion and myeloid-derived suppressor cell activation, collectively shaping a profoundly immunosuppressive tumour microenvironment. Mechanistically, CD70 expression is amplified by convergent oncogenic, inflammatory and hypoxic signals, most notably HIF-2α stabilization in VHL-deficient RCC, linking it to aggressive disease biology and poor prognosis. Notably, CD70 expression in tumours often coexists with dysregulation of receptor tyrosine kinase (RTK) pathways (e.g. MET, AXL) and immune checkpoint circuits (e.g. PD-1/PD-L1), supporting rationale combination therapies aimed at overcoming resistance and enhancing anti-tumour immunity. A diverse array of CD70-directed therapies, including antibody-drug conjugates, CAR-T and CAR-NK cells, monoclonal antibodies and radiotheranostic agents, are advancing through preclinical and early clinical pipelines. Beyond therapeutic applications, CD70 also holds promise as a biomarker for tumour detection, patient stratification and response monitoring. This mini-review synthesizes emerging insights into CD70-driven immune evasion, highlights evolving therapeutic strategies and discusses the integration of CD70 targeting into next-generation immunotherapy and precision oncology platforms. This review is novel in linking CD70-mediated immune escape to oncogenic RTK signalling and in foregrounding recent translational advances and rational combination strategies that have not been comprehensively covered in prior reviews.

Mammalian oocyte meiosis holds distinct features from mitosis in many aspects. For example, the organisation of the spindle poles, the separation processes of the chromosomes, the way microtubules (MTs) are nucleated and so forth.¹ Many issues about oocyte meiosis are still to be addressed. Moreover, in the past decade, researchers found that oocyte meiosis in primates, including humans, employed some specific proteins or structures, making the mechanical study of mammalian oocyte meiosis more complicated.^2-4 Among these primate-specific proteins, TUBB8 is the most conspicuous since the Tubb8 mutation in humans accounts for about 30% or more of abnormal clinical cases in MI arrest, fertilisation failure, and early embryo development arrest.^{5, 6} However, there are still many unaddressed questions about TUBB8. For example, what's the exact mechanism by which TUBB8 function to organise and stabilise spindle MTs? Are there effective and easy strategies to rescue all sorts of spindle defects caused by different TUBB8 mutations? Recently, a work by Hui Luo et al has made significant progress on both questions.⁷

For the first question, through a combination of multiple cell biological & molecular biology, and biochemistry techniques, they found that TUBB8-D417N expression significantly disrupted its interaction with EB1, a fundamental MT nucleator and polymerizer, and thereby dis-localised EB1; meanwhile, the EB1 protein level didn't change, suggesting that TUBB8 help the correct localisation of EB1. EB1 mislocalisation in turn seriously disrupted the distribution of several other MT nucleators, including CKAP5 and TACC, but didn't affect their protein levels (Figure 1). In addition, TUBB8-D417N expression also broke up the localisation of several critical MT polymerisers and stabilisers, including TPX2, Ran-GTP and KIF11. All these suggest that TUBB8 is fundamentally important for MT nucleation & polymerisation and the maintenance of spindle bipolarity.

Nonetheless, it's this study that incites the upper issues, and many others. Therefore, it is a very important and enlightening work. It would be exciting to expect further related investigations. Figure 1

Zhi-Xia Yang wrote the manuscript and made the graphic abstract image. Dong Zhang and Zi-Fu Wang proofread and gave advice. All authors read and approved the final manuscript.

The authors declare no conflict of interest.

Not applicable.

Intravital microscopy enables dynamic and real-time visualisation of microscopic structures in living tissues without the need for fixation, with real-life applicability being illustrated by several first-in-human studies in different cancers. Its use in preclinical models has yielded important observations of the microvasculature of both healthy and diseased tissues. It has further enabled the observation of the interactions between important components of the tissue microenvironment such as immune cells and neighbouring microvessels. Important recent technological advances, however, have enabled the translation of this technology to human use. Here, we review the main advances in intravital microscopy and some of the most recent uses in different human disease settings.