Relapsed and refractory paediatric brain tumors—including high-grade gliomas (HGG) such as diffuse hemispheric glioma, diffuse midline glioma (DMG), diffuse intrinsic pontine glioma (DIPG), and atypical teratoid rhabdoid tumors (AT/RT), medulloblastoma (MB) and ependymoma (EPN)—remain among the most treatment-resistant childhood malignancies. Despite multimodal therapy combining maximal safe resection, radiotherapy, and chemotherapy, long-term survival after relapse is exceedingly rare. The limitations of conventional cytotoxic regimens and the largely immune-silent nature of these tumors have driven interest in therapeutic vaccination as a strategy to induce durable, antigen-specific immune responses. Advances in molecular profiling and immunopeptidomics have enabled the identification of tumor-exclusive peptides, even within the low-mutational landscape typical of paediatric gliomas. Preclinical investigations demonstrate that dendritic-cell- (DC), peptide-, or mRNA-based vaccines can elicit tumor-specific cytotoxic T-cell responses and modify the tumor microenvironment. Early clinical experiences in relapsed paediatric HGG and DMG indicate safety and feasibility, with emerging evidence of immune activation and prolongation of survival. Features of paediatric immunity render children particularly responsive to cancer vaccines and insights from paediatric trials may prove valuable for the design of immunotherapeutic strategies in aging-related cancers. This review summarizes current preclinical and clinical developments in paediatric brain-tumor vaccination, focusing on antigen discovery, immunologic mechanisms, vaccine platforms, and translational challenges that define this evolving frontier in paediatric neuro-oncology.

Pancreatic cancer is a highly aggressive and lethal malignancy with an exceptionally poor prognosis. Its clinical management is severely hampered by insidious early symptoms, strong invasiveness, intrinsic chemoresistance, and limited efficacy of conventional therapies. Carbon dots (CDs) have shown great promise in precision cancer theranostics owing to their excellent optical properties, high biocompatibility, controlled drug loading and release capabilities and customizable targeting features. This review critically examines the major therapeutic barriers in pancreatic cancer management, systematically summarizes the applications of CDs in pancreatic cancer imaging, targeted drug delivery, hyperthermia and pH-responsive theranostics, analyzes the current limitations of CD-based nanosystems, and discusses future development directions. This work aims to provide a rigorous theoretical foundation for the rational design and development of novel CD-mediated precision intervention strategies for pancreatic cancer.

DNA replication constantly faces obstacles that threaten genome stability. Faithful duplication requires replication forks to smoothly process template damage, chemical or topological blocks, and repair intermediates. Traditionally, replication-associated lesions are described by their initial structures (nicks, gaps, etc.). However, their S-phase identities are highly transitional: a template single-strand break (SSB) can become a one-ended double-strand break (DSB) upon fork arrival, a replication fork stalled by a template block can reverse, restart, or collapse, and a repriming event leaves a post-replicative single-stranded DNA (ssDNA) gap. The biological consequence of a lesion depends heavily on its structural transitions and how it is “routed” through distinct repair, bypass, or cleavage pathways. In this review, we shift our focus from static structural identities to dynamic lesion routing, emphasizing the coordination between SSB repair (SSBR) and DSB repair (DSBR). We first summarize the major sources of replication-associated strand lesions, and then discuss how strand lesions are managed across three processing windows: SSBR before fork encounter, the overlap zone in which gaps and stressed forks can be buffered without immediate DSB conversion, and broken-fork/DSBR-centered processing after DSB formation, including homologous recombination (HR)-mediated restart, break-induced replication (BIR)-like synthesis, or end joining. Depending on the routing network, lesion processing can result in accurate completion, delayed resolution or salvage, mutagenic completion, structural genome scars, or cytotoxic genome instability. Finally, we discuss how this dynamic framework refines our understanding of DNA damage response (DDR)-targeted cancer therapies, drug resistance, and treatment outcomes in different genetic or therapeutic contexts.

DNA replication and transcription operate on the same chromatin template and inevitably interfere with one another, giving rise to transcription-replication conflicts (TRCs), an important endogenous source of replication stress and genome instability. Although head-on (HO) conflicts are generally more disruptive than co-directional (CD) encounters, orientation alone does not determine the outcome. Gene architecture, transcriptional activity, replication timing, chromatin environment, DNA topology, and R-loop dynamics can all influence whether an approaching replication fork pauses, collapses, or traverses a transcribed region. Recent single-molecule, genomic, and biochemical studies further suggest that some CD encounters can be traversed under favorable topological and transcriptional conditions, although the mechanisms that permit such bypass and their broader biological significance remain incompletely understood. Here, we discuss TRC control within an operational framework comprising prevention, resolution, tolerance, and recovery. We examine how cells coordinate replication and transcription in space and time, regulate R-loop formation and turnover, protect or remodel challenged forks and chromatin, and modify or remove transcription complexes at conflict sites. We also consider how emerging single-molecule and multi-omic approaches can distinguish transient fork pausing from persistent pathological conflicts. Finally, we discuss the contributions of TRCs to cancer-associated chromosomal instability, cellular senescence, and neurodegenerative disease, and highlight the questions that must be resolved to understand how cells preserve genome integrity when replication and transcription compete for the same DNA template.

The tumor immune microenvironment (TIME) is a principal determinant of tumor progression, metastatic dissemination, and therapeutic response. Cellular senescence, primarily through the senescence-associated secretory phenotype (SASP), progressively reshapes the TIME toward immunosuppressive and therapy-resistant states. Here, we propose an integrative framework of “senescence-associated transcriptional reprogramming” comprising three mechanistic layers: endogenous inflammation-driven signaling centered on the cGAS-STING-NF-κB-IFN hub; lineage-specific epigenetic lock-in in immune cells; and metabolic-epigenetic coupling. We further discuss mechanism-guided, temporally optimized senolytic and senomorphic strategies, particularly relevant to elderly cancer patients, to rationally reverse senescence-driven tumor immune tolerance and enhance current immunotherapies.

The tumor immune microenvironment (TIME) is a central determinant of cancer progression and therapeutic response. Although organoid and organ-on-a-chip technologies have substantially advanced the modeling of tumor-immune interactions, most current platforms overlook a critical dimension of clinical reality: immunosenescence. This process profoundly reshapes immune cell composition, functional capacity, and tumor-immune crosstalk, yet it remains largely absent from existing in vitro systems. In this review, we provide a conceptual and methodological overview of organoid- and microfluidic-based models for reconstructing the TIME. We highlight their respective strengths in capturing tumor heterogeneity and dynamic immune processes, while critically evaluating their limitations in modeling long-term immune evolution and age-associated dysfunction. Importantly, we propose immunosenescence as a missing but essential modeling axis and argue that it should be treated as a controllable experimental variable rather than a background condition. By integrating aging-associated immune features into advanced 3D and microfluidic platforms, next-generation models are poised to better recapitulate patient heterogeneity and improve the prediction of immunotherapy outcomes. This perspective underscores a shift toward age-aware, physiologically relevant tumor models and provides a framework for advancing precision immuno-oncology in an aging population.

The rising incidence of age-related brain pathologies, including brain malignancy, underscores an urgent need to understand the mechanistic interplay between aging and tumorigenesis. Historically viewed as distinct entities, brain tumors and neurodegenerative disorders are now recognized to share key biological processes, such as cellular senescence, chronic inflammation, and metabolic dysregulation. In this review, we deconstruct the existing knowledge at the intersection of cancer neuroscience and aging biology, and propose that age-related alterations in neuronal function, such as the accumulation of senescent cells, ion channel dysregulation, and neurotransmitter imbalance, are not inert background features but as active mediators of tumor progression and treatment resistance. We summarize the aged neural microenvironment, marked by a proinflammatory senescence-associated secretory phenotype (SASP) and blood-brain barrier dysfunction, underlies a permissive soil for malignancy. Moreover, we highlight the emerging concept that tumors can induce a pathological aging phenotype in surrounding neurons, which in turn potentiates the observed cognitive deterioration. By framing brain tumors as products of a dysfunctional aging ecosystem, we propose therapeutic strategies that target convergent aging mechanisms through senolysis, metabolic reprogramming, and neurotransmitter modulation may simultaneously achieve tumor control and preserve cognitive function. This integrated perspective opens new avenues for repurposing neuroactive drugs and designing interventions that address the sophisticated biology of the aging brain and malignancy.

Aging remains the primary risk factor for malignancy, driven primarily by the progressive decline of the immune system known as immunosenescence. Natural killer (NK) cells serve as the critical effectors of tumor immunosurveillance, yet their anti-tumor efficacy is compromised during biological aging. This review delineates the multifaceted mechanisms of NK cell immunosenescence including phenotypic subset redistribution, receptor signaling dysregulation, and metabolic biogenesis failure driven by mitochondrial impairment alongside telomere attrition and p16 p21 mediated cell cycle arrest. These cell intrinsic defects interact with the suppressive aging microenvironment to create a self-reinforcing vicious cycle that facilitates tumor escape in the elderly population. Breaking this cycle necessitates a multi-dimensional therapeutic framework that integrates cellular rejuvenation via induced pluripotent stem cell (iPSC) derived chimeric antigen receptor (CAR) NK cells with niche remodeling using senolytics or bone marrow rejuvenation. Ultimately targeting the biological hallmarks of NK cell immunosenescence represents a significant frontier in geriatric oncology offering the potential to resuscitate anti-tumor immunity for the burgeoning elderly population.

Homologous recombination (HR) is a high-fidelity DNA repair pathway that preserves genome stability through the accurate repair of DNA double-strand breaks. RAD51 is the central recombinase of HR and catalyzes the key processes of homology search and strand invasion through the formation of nucleoprotein filaments on single-stranded DNA. The assembly, stability, and disassembly of RAD51 filaments are tightly regulated by a complex network of mediators, cofactors, and anti-recombinases, ensuring efficient DNA repair while preventing aberrant recombination. Beyond its canonical role in HR, RAD51 also contributes to replication fork protection and replication stress responses. Dysregulation of RAD51 activity can lead to genome instability, cancer development, hereditary disorders, and cellular senescence. Conversely, elevated RAD51 expression frequently promotes therapeutic resistance in tumors. In this review, we summarize the molecular mechanisms of RAD51-mediated HR repair, discuss the regulatory pathways that control RAD51 activity and dynamics, examine its roles in genome stability and human disease, and highlight recent advances in therapeutic strategies targeting RAD51 and the HR pathway. Understanding the multifaceted functions of RAD51 will facilitate the development of more effective DNA repair-directed cancer therapies.