N 4 -acetylcytidine (ac 4 C) is a highly conserved RNA modification that has emerged as a post-transcriptional regulator of gene expression. N-acetyltransferase 10 (NAT10) is the sole known enzyme catalyzing ac 4 C deposition on RNA, and its aberrant overexpression is implicated in multiple malignancies. This review critically synthesizes current evidence on NAT10-mediated ac 4 C modification in cancer, focusing on its molecular mechanisms, role in metabolic reprogramming, and therapeutic potential. We systematically evaluate the mechanistic basis of ac 4 C deposition and its functional consequences on mRNA stability and translation. We then assess the landscape of NAT10 dysregulation across cancers, distinguishing established oncogenic drivers from correlative findings. The emerging role of NAT10 in remodeling glycolysis, lipid metabolism, and mitochondrial function is examined, highlighting specific downstream targets and their context-dependent significance. We critically appraise current therapeutic strategies, from small-molecule inhibitors (e.g., Remodelin) to the novel PROTAC degrader NP1192, discussing their preclinical efficacy, limitations, and the significant knowledge gaps that remain. Finally, we explore the complex interplay between NAT10 and the tumor immune microenvironment, evaluating the potential and challenges of combining NAT10-targeted therapies with immunotherapy. A key focus is identifying unresolved controversies, such as the existence of ac 4 C erasers, the lack of independent validation for many reported targets, physiological risks including gonadal toxicity upon systemic NAT10 inhibition, to guide future research toward clinically meaningful advances.
The integrated stress response (ISR), a conserved cellular sentinel, is pathologically commandeered in cancer to sustain survival under chronic duress. Here, we posit that tumors evolve a state of "ISR Addiction", a profound, non-oncogenic dependency on persistent ISR signaling orchestrated through sustained eIF2α phosphorylation and ATF4-driven transcription. We delineate a three-stage continuum—utilization, dependence, and fixation—tracing how this addiction emerges under microenvironmental pressure and becomes entrenched during therapy. This dependency actively fuels metastasis and acts as a central hub for resistance to chemotherapy, targeted agents, and immunotherapy. Expanding this view, we embed ISR addiction within a multilayered "Ecosystem of Tumor Addictions", where bidirectional crosstalk with redox addiction (maintaining biochemical balance) and neural addiction (processing systemic signals) collectively creates a buffered resilience network. Crucially, this ecosystem reveals a therapeutically exploitable fragility: the addicted state is maintained in a precarious "Goldilocks" balance ("Goldilocks" refers to a "just right" condition—not too much, not too little—borrowed from the children’s tale Goldilocks and the Three Bears, where the protagonist finds the porridge that is neither too hot nor too cold, but perfectly suited), susceptible to either "enforced withdrawal" (blocking pro-survival ATF4 outputs) or "toxic overload" (hyperactivating the pro-apoptotic CHOP arm). We propose that rational combinations targeting this addiction network, particularly with standard-of-care or immunomodulatory agents, offer a transformative strategy to dismantle the resilient core of advanced malignancies.
N4-acetylcytidine (ac4C) is a highly conserved RNA modification that has emerged as a post-transcriptional regulator of gene expression. N-acetyltransferase 10 (NAT10) is the sole known enzyme catalyzing ac4C deposition on RNA, and its aberrant overexpression is implicated in multiple malignancies. This review critically synthesizes current evidence on NAT10-mediated ac4C modification in cancer, focusing on its molecular mechanisms, role in metabolic reprogramming, and therapeutic potential. We systematically evaluate the mechanistic basis of ac4C deposition and its functional consequences on mRNA stability and translation. We then assess the landscape of NAT10 dysregulation across cancers, distinguishing established oncogenic drivers from correlative findings. The emerging role of NAT10 in remodeling glycolysis, lipid metabolism, and mitochondrial function is examined, highlighting specific downstream targets and their context-dependent significance. We critically appraise current therapeutic strategies, from small-molecule inhibitors (e.g., Remodelin) to the novel PROTAC degrader NP1192, discussing their preclinical efficacy, limitations, and the significant knowledge gaps that remain. Finally, we explore the complex interplay between NAT10 and the tumor immune microenvironment, evaluating the potential and challenges of combining NAT10-targeted therapies with immunotherapy. A key focus is identifying unresolved controversies, such as the existence of ac4C erasers, the lack of independent validation for many reported targets, physiological risks including gonadal toxicity upon systemic NAT10 inhibition, to guide future research toward clinically meaningful advances.
Transmembrane serine protease 4 (TMPRSS4) is associated with poor prognosis in multiple cancers, including non-small cell lung, pancreatic, and colorectal cancers. We previously showed that TMPRSS4 promotes cancer stem-like properties in prostate cancer in a manner dependent on epithelial–mesenchymal transition (EMT) transcription factors. Here, we identified a novel TMPRSS4–EMT transcription factor–KRAS axis that drives cancer stem-like features and tumorigenesis in colon and lung cancers. TMPRSS4 knockdown suppressed tumor growth and cancer stem-like properties, accompanied by reduced KRAS expression and decreased phosphorylation of ERK1/2 and AKT, consistent with transcriptomic analysis showing activation of RAS, MAPK, and PI3K–AKT signaling pathways by TMPRSS4. Mechanistically, the EMT-inducing transcription factors SLUG and TWIST1 were required for TMPRSS4-mediated KRAS upregulation. These factors enhanced KRAS transcription through the E-box element within the intron 1 regulatory region of KRAS and increased KRAS expression post-transcriptionally via repression of KRAS-targeting miR-200c. Clinically, TMPRSS4 expression positively correlated with KRAS expression, and co-expression of TMPRSS4 and KRAS was associated with poor survival across multiple cancers. Together, these findings reveal a previously unrecognized TMPRSS4–SLUG/TWIST1–KRAS pathway that promotes tumor progression, highlighting the TMPRSS4–KRAS axis as a potential therapeutic target for cancers driven by KRAS mutation and/or elevation.
Tumor heterogeneity remains a major bottleneck for effective cancer therapy because many determinants of target expression, biomarker performance, and treatment resistance are spatially organized within the tumor ecosystem. Bulk molecular profiling averages these signals across cell populations, whereas dissociation-based single-cell approaches disrupt the tissue architecture that shapes cell state, signaling, and drug access. Spatial multi-omics addresses these limitations by mapping transcriptomic, proteomic, metabolomic, and epigenomic features in situ, while AI enables integration of these modalities with histology, spatial coordinates, and clinical outcomes. Current evidence suggests that graph-based and neighborhood-aware models are most useful for spatial domain detection and niche mapping, whereas multimodal and histology-based models require stronger external validation before clinical deployment. In this review, we examine how spatial multi-omics and AI are redefining tumor heterogeneity as a translational variable in oncology. We focus on target discovery, patient stratification, and resistance biology. We also discuss major barriers to clinical translation, including platform bias, FFPE compatibility, assay cost, molecular coverage, segmentation and registration errors, limited benchmarking, domain shift, and the need for independent multicenter validation.
