O-linked N-acetylglucosamine protein modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification frequently upregulated in cancers. Autophagy, a lysosome-dependent recycling pathway, plays a context-dependent dual role in tumorigenesis and therapy resistance. Emerging evidence reveals intricate crosstalk between these two processes, positioning the O-GlcNAcylation-autophagy axis as a critical regulator of cancer cell adaptation.
This review systematically delineates the multidimensional mechanisms by which O-GlcNAcylation regulates distinct stages of autophagy initiation, maturation, and fusion across various cancer types. We detail how O-GlcNAcylation targets core autophagy machinery, including the ULK1 complex, LC3 lipidation system, and SNARE fusion proteins, and modulates key signaling hubs like mTOR and AMPK. Furthermore, we integrate this molecular regulation with the stage-specific pro-tumor or tumor-suppressive functions of autophagy, highlighting how O-GlcNAcylation remodels autophagic flux to promote metabolic reprogramming, stress survival, and therapeutic resistance.
The O-GlcNAcylation-autophagy axis represents a promising therapeutic target. Combining small-molecule inhibitors of O-GlcNAc cycling enzymes (OGT/OGA) with autophagy modulators offers a novel strategy to overcome tumor drug resistance. Future research must address the heterogeneity of this regulatory network across cancer types and developmental stages to advance precision oncology interventions.
Synthetic lethality (SL)-based strategies hold significant promise for overcoming therapeutic resistance, a critical bottleneck in cancer treatment where cancer cells evade anticancer therapies, leading to diminished efficacy or treatment failure. The core of SL lies in exploiting tumour-specific vulnerabilities: drug-resistant cells often acquire unique genetic defects or compensatory adaptive responses, and SL strategies selectively target genes or pathways dependent on these vulnerabilities to induce specific cell death, thereby reversing resistance.
This review systematically elaborates on SL mechanisms and the multi-faceted nature of tumour drug resistance, then focuses on how SL counteracts resistant phenotypes by leveraging resistant cells’ vulnerabilities. We further delineate SL applications in preclinical resistance models, highlight representative SL-related drugs and predictive biomarkers and critically analyse challenges in clinical translation.
By integrating mechanistic insights, preclinical validation and translational perspectives, this review aims to provide novel insights for precision therapy and a foundational reference to advance SL strategies in overcoming tumour resistance and facilitating their clinical implementation.
Elevated lactate is associated with vascular endothelial dysfunction, a factor that can contribute to organ failure in sepsis. However, the specific mechanisms involved have yet to be fully elucidated. Here, we investigated the role of enolase 1 (ENO1) lactylation in modulating the functions of endothelial cells (ECs) in sepsis pathogenesis.
The septic mouse model was established using two methods: cecal ligation and puncture (CLP) and intraperitoneal injection of LPS. AAV-ENO1 shRNA was administered to ablate ENO1 in vascular endothelial cells of mice. Tail vein injection of .5% Evans Blue Dye (EBD) was utilised to assess microvascular permeability in septic mice. Post-translational modification (PTM) mass spectrometry was employed to detect key proteins undergoing lactylation in endothelial cells. Additionally, CCK-8 assay, Transwell assay, and scratch wound healing assay were performed to evaluate the fundamental functions of ECs. Further investigations were conducted through Western blotting, Co-immunoprecipitation (CO-IP), RT-qPCR, RNA immunoprecipitation (RIP) and RNA sequencing to examine genes/proteins involved in vascular endothelial injury and their interactions.
We found that elevated lactate in sepsis promoted the lactylation of ENO1 at the K71 residue, facilitated by the increased activity of the lactyltransferase P300. This modification reduced the binding of TRIM21 mRNA to ENO1, thereby preventing its degradation by limiting the recruitment of CNOT6. Consequently, the stability and expression of TRIM21 mRNA were enhanced. Elevated TRIM21 subsequently binds to vascular endothelial-cadherin (VE-Cadherin), promoting its ubiquitination and degradation, disrupting endothelial adherens junctions (AJs) and increasing endothelial permeability. Targeting the lactylation of ENO1 at K71 with a specific inhibitory peptide alleviated endothelial injury and improved survival rates in septic mice.
These findings suggest that ENO1 lactylation plays a pivotal role in vascular endothelial dysfunction during sepsis. Inhibiting lactylation may offer a therapeutic strategy for sepsis treatment.
In colorectal cancer (CRC), innate lymphoid cells (ILCs) play a vital role in preserving and modulating immune homeostasis within the intestinal environment. However, the origins and diverse functions of ILCs in CRC remain poorly understood, making it difficult to clarify how these cells contribute to disease progression and influence therapeutic efficacy.
Single-cell RNA sequencing (scRNA-seq) generated an atlas of ILCs from multiple tissues (bone marrow, blood, and intestine), revealing their origins, heterogeneity, and plasticity. Spatial transcriptomics (ST) and immunofluorescence (IF) defined their specific cellular neighbourhoods within the tumour microenvironment. In vitro co-culture assays were performed to validate the regulatory role of ILC2s in B cell maturation. Bulk RNA sequencing and flow cytometry were employed to assess the survival and therapeutic response potential of ILCs.
Intestinal ILCs have two distinct origins: ILC3-CD83 cells derived from the fetal gut, which persist into adulthood; and ILC2 and ILC3-S100A4 cells that might originate from the bone marrow and migrate through the circulation to colonise intestinal tissues. The tissue-resident ILC3 subsets exhibited diverse functional roles in CRC. Specifically, trajectory analysis showed that ILC3s differentiated into either stress-responsive ILC3-HSPA1B cells or cytotoxic ILC1/NK cells in CRC. Additionally, by using spatial transcriptomics analysis combined with functional assays, we found that bone marrow-derived ILC2s preferentially localise in tertiary lymphoid structures (TLSs), where they likely support B cell maturation. Notably, higher ILC2 abundance correlated with better clinical outcomes and greater therapeutic benefit.
This study reveals the distinct origins and functional heterogeneity of intestinal ILC subsets in CRC. The enrichment of bone marrow-derived ILC2s in TLSs, where they likely support B cell maturation, is associated with improved prognosis and favourable immunotherapy response, which may serve as biomarkers for survival and therapeutic efficacy in CRC.
Angiogenesis, driven by the vascular endothelial growth factor (VEGF)/VEGFR signalling axis under hypoxic conditions, is one of the hallmarks of ovarian cancer (OC), contributing to tumour progression, metastatic dissemination and immune evasion. Hypoxia-induced angiogenic signalling sustains tumour growth and shapes an immunosuppressive tumour microenvironment, while homologous recombination deficiency (HRD) has been associated with increased tumour hypoxia and pro-angiogenic signalling. Conversely, VEGF pathway inhibition may exacerbate DNA damage and modulate immune cell trafficking, providing a strong biological rationale for synergy between anti-angiogenic agents, PARP inhibitors (PARPi), and immune checkpoint inhibitors. Bevacizumab, a humanised monoclonal antibody targeting VEGF-A, represents a pivotal therapeutic agent in OC management by inhibiting tumour angiogenesis and inducing transient vascular normalisation. Its clinical efficacy has been demonstrated as maintenance therapy in the first-line setting, alone or in combination with PARPi for HRD-positive disease, and in the recurrent setting both in platinum-sensitive and platinum-resistant disease. Despite these benefits, variability in patient response highlights the unmet need for validated predictive biomarkers. Circulating, tissue-based and molecular biomarkers have been investigated, including angiogenic factors (Tie2/Ang1 axis, interleukin-6 [IL-6] and chitinase-3-like protein [YKL-40]), VEGF-A isoforms, microvessel density, EGFR/ADAM17 signalling, angiomiRs and transcriptional subtypes with mesenchymal and proliferative phenotypes showing greater sensitivity to anti-angiogenic strategies. Although HRD status holds prognostic relevance and selected microRNAs show emerging potential, no biomarker has yet been validated to predict benefit from bevacizumab in clinical practice. Translational analyses from the MITO16A/MaNGO OV-2 program, highlight challenges such as assay standardisation, multiplicity correction and external validation, while identifying tumour immune infiltration patterns, TP53 mutation classes and composite HRD assessments as areas of further investigation. In conclusion, bevacizumab remains an integral component of OC treatment. Future progress will depend on biomarker-driven, prospectively designed clinical trials and the integration of multi-omic data and machine learning approaches to enable precision application of anti-angiogenic strategies, maximising clinical benefit while minimising toxicity.
BRD7 has been confirmed to be lowly expressed in nasopharyngeal carcinoma (NPC) tissues and exerts tumour suppressive roles. However, the molecular mechanism of the downregulation of BRD7 expression and whether the strategy of activating BRD7 expression plays anti-tumour effects still needs to be clarified.
Methylation-specific polymerase chain reaction (PCR) was used to identify the methylation levels of BRD7 promoter. In vitro experiments were used to evaluate the effects of BRD7-targeted demethylation system on the malignant progression of NPC cells. Chromatin immunoprecipitation (ChIP)-qPCR experiment was employed to examine the regulatory mechanisms underlying the demethylation system. Xenograft tumour models were used to assess impact of this demethylation system on tumour growth in vivo and the anti-tumour effects of the lentivirus-mediated demethylation system in NPC.
There was hypermethylation modification in BRD7 promoter, which was negatively correlated with BRD7 expression. Next, we constructed a LentiCRISPRv2/dCas9-TET1CD-sgRNAs system targeting specific methylation sites of BRD7 promoter based on five sgRNAs, and confirmed that all five sgRNA-guided CRISPR/dCas9 systems could activate BRD7 and inhibit cell proliferation to varying degrees, among which sgRNA2&sgRNA5 were the most significant. Further, we constructed NPC cell lines stably transfected with LentiCRISPRv2/dCas9-TET1CD-sgRNA2&5, and confirmed that both sgRNA2&sgRNA5 could promote the transcriptional activation by reducing its methylation, and inhibit the cell proliferation, migration, invasion and tumour growth in vivo of NPC, and the combination of them has a more significant demethylation, transcriptional activation and anti-tumour effect. In addition, BRD7 had hypermethylation modification in its promoter and decreased expression in NPC tissues, and both of them were negatively correlated, making it a potential diagnostic marker for NPC diagnosis.
The hypermethylation modification of BRD7 is an important mechanism leading to the inactivation of BRD7, and targeting demethylation of BRD7 inhibits the malignant progression of NPC, which might be a promising targeted therapeutic approach for treating NPC.
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