Radiotherapy is one of the most common treatments for oral cancer. However, in the clinic, recurrence and metastasis of oral cancer occur after radiotherapy, and the underlying mechanism remains unclear. Cancer stem cells (CSCs), considered the “seeds” of cancer, have been confirmed to be in a quiescent state in most established tumours, with their innate radioresistance helping them survive more easily when exposed to radiation than differentiated cancer cells. There is increasing evidence that CSCs play an important role in recurrence and metastasis post-radiotherapy in many cancers. However, little is known about how oral CSCs cause tumour recurrence and metastasis post-radiotherapy. In this review article, we will first summarise methods for the identification of oral CSCs and then focus on the characteristics of a CSC subpopulation induced by radiation, hereafter referred to as “awakened” CSCs, to highlight their response to radiotherapy and potential role in tumour recurrence and metastasis post-radiotherapy as well as potential therapeutics targeting CSCs. In addition, we explore potential therapeutic strategies targeting these “awakened” CSCs to solve the serious clinical challenges of recurrence and metastasis in oral cancer after radiotherapy.

In the ever-evolving landscape of cancer therapy, while cancer treatments such as chemotherapy, radiotherapy, and targeted therapy aim to eradicate malignant cells, they also inadvertently trigger cellular senescence in both cancerous and microenvironmental tissues. Therapy-induced senescence (TIS) can act as a barrier against tumor growth by halting cell proliferation in the short term, but the long-term persistence of therapy-induced senescent (TISnt) cells may pose a significant challenge in cancer management. Their distinct characteristics, like senescence-associated secretory phenotype (SASP), metabolic dysregulation, and immune evasion, make them exhibit remarkable heterogeneity to orchestrate the tumor microenvironment (TME), resulting in therapy resistance. However, how these TISnt cells functioning differently in cancer progression, and the intricate mechanisms by which they remodel the senescence-associated immunosuppressive microenvironment present challenges for improving anticancer therapy. Therefore, this review summarizes the heterogeneous TISnt cell phenotypes contributing to an accumulated senescent state, outlines their multidimensional interactions in the senescent microenvironment, and discusses current senescence-targeting strategies. Building on the current understanding of TIS, we propose potential avenues for improving TIS-targeting methodologies in the context of head and neck cancer, a representative heterogeneous malignancy, which can substantially enhance the efficacy of the “one-two punch” sequential treatment approach for head and neck cancer.

Background: The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. Methods: The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. Results: We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3β collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback. Conclusions: Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.

A slow-growing, scotochromogenic mycobacterial strain (24^T) was isolated from the sputum of a Chinese male human. Phylogenetic analysis using the 16S rRNA gene assigned strain 24^T to the Mycobacterium gordonae complex, which includes Mycobacterium gordonae and Mycobacterium paragordonae . The phenotypic characteristics, unique mycolic acid profile and the results of phylogenetic analysis based on hsp65 and rpoB sequences strongly supported the taxonomic status of strain 24^T as a representative of a species distinct from the other members of the M. gordonae complex. The genomic G+C content of strain 24^T was 65.40mol%. Genomic comparisons showed that strain 24^T and M. gordonae ATCC 14470^T had an average nucleotide identity (ANI) value of 81.00 % and a DNA–DNA hybridization (DDH) value of 22.80 %, while the ANI and DDH values between strain 24^Tand M. paragordonae 49 061^T were 80.98 and 22.80 %, respectively. In terms of phylogenetic, phenotypic and chemotaxonomic features, strain 24^T is distinguishable from its closest phylogenetic relatives and represents a novel species of the genus Mycobacterium , therefore the name Mycobacterium vicinigordonae sp. nov. is proposed. The type strain is 24^T (=CMCC 93559^T=DSM 105979^T).

Precancers, defined as normal-appearing or morphologically altered tissues with a risk of oncogenesis, exhibit various detectable manifestations across anatomical sites, including epithelial dysplasia, metaplasia, hyperplasia, and stromal fibrosis. Considering the prevailing assumption that most cancers arise from precancers, early intervention at the precancerous stage has immense potential to reduce cancer-related morbidity and mortality. However, the complex signaling networks governing precancer initiation and progression remain elusive, hampering the development of effective targeted interventions. This review synthesizes three critical dimensions of precancer biology: historical foundations tracing the conceptual evolution of precancer research over the past century; mechanisms underlying the multistep progression of precancer biology, encompassing epithelial and macro/microenvironmental remodeling; and signaling networks cataloging dysregulated pathways and their therapeutic potential. Over 10 signaling pathways, including the transforming growth factor-β (TGF-β), p53, Wnt, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways, drive multistep malignant transformation. We further synthesize emerging evidence supporting microenvironmental dominance, proposing the novel “soil degeneration” hypothesis. This paradigm shift underscores the necessity for dual-window intervention in which early-phase microenvironmental normalization prevents the establishment of precancerous lesions and advanced-phase treatment concurrently addresses epithelial malignancy and stromal degeneration. This review bridges foundational molecular discoveries with translational clinical potential and advocates for precision intervention frameworks that extend from biomarker-guided risk assessment to synergistic remodeling of the precancer microenvironment, thereby redefining precancer intervention in the molecularly targeted era.