Digestive system tumor, including esophageal tumor, gastric tumor, intestinal tumor, liver tumor, pancreatic tumor, and cholangiocarcinoma, are the most common tumors worldwide and serve as a major cause of tumor-related death. Cancer stem cells (CSCs) are a small group of cells in tumors that harbor self-renewal, differentiation abilities, playing a crucial role in tumor initiation, progression, metastasis, and are supposed to be the fundamental cause of tumor recurrence after conventional treatment. A comprehensive understanding and targeting of CSCs is the key to overcoming tumors. In this review, focusing on digestive system tumors, we summarize the characteristics of CSCs, review the intracellular mechanisms that regulate self-renewal and functional maintenance of CSCs, including stemness pathways, transcription and epigenetic regulation, metabolic regulation, and noncoding RNAs, and demonstrate microenvironmental regulation and systemic regulation of CSCs at molecular and cellular levels. Finally, we summarize recent advances in tumor therapy with CSC targeting and their niche remodeling. These research progress on CSCs in digestive system tumors provide crucial insights into the occurrence, development, drug resistance, recurrence and metastasis of tumors, and offers new targeted treatment strategies for defeating tumors.

Liquid–liquid phase separation (LLPS) plays a critical role in orchestrating various cellular processes, such as gene expression, signal transduction, and protein synthesis, by compartmentalizing cellular components without membrane boundaries. Emerging research has illuminated how dysregulated LLPS is integral to cancer development by influencing tumorigenesis, metastasis, immune system evasion, and resistance to therapy. The subtle differences in LLPS are crucial for understanding cancer progression and finding new treatments. However, despite its significant implications in oncology, the potential of specifically targeting LLPS in cancer therapy has not been thoroughly investigated. This review delves into the mechanisms of LLPS, exploring physiological triggers and their consequences in cancer biology. We discuss the profound impact of LLPS on the hallmarks of cancer and outline innovative strategies aimed at targeting LLPS. These strategies include the direct inhibition of phase condensate formation and the modulation of related signaling pathways. Although targeting LLPS poses several challenges, such as specificity and delivery methods, it represents a promising frontier in cancer treatment, potentially revolutionizing how we approach cancer therapy. This review emphasizes the academic and therapeutic importance of LLPS, advocating for it as an exciting and valuable target for future cancer treatment strategies.

Osimertinib is the only third-generation EGFR tyrosine kinase inhibitor clinically approved for first-line treatment of advanced NSCLC patients harboring EGFR mutations. However, drug resistance severely hinders its clinical efficacy. Acquired MET amplification is an important mechanism causing osimertinib resistance. This study is the first to identify fexofenadine, originally indicated for allergic rhinitis and chronic urticaria, as a putative Met-inhibitor by in silico chemical-protein interactome analysis of known Met inhibitors. Fexofenadine was verified to inhibit recombinant Met kinase in cell-free assay and phosphorylation of Met and other downstream signaling molecules in osimertinib-resistant NSCLC cell lines. KINOME profiling revealed a similar kinase inhibition profile between fexofenadine and a known Met-inhibiting drug cabozantinib using Spearman rank-order correlation analysis. Among the tested osimertinib-resistant NSCLC cell lines, fexofenadine was the most efficacious in potentiating osimertinib in NCI-H820 (having MET amplification and EGFR-T790M mutation). Transcriptome profiling in NCI-H820 revealed that the differentially expressed genes following fexofenadine treatment were enriched in epithelial-mesenchymal transition-related biological pathways. Importantly, fexofenadine was also shown to significantly potentiate the antitumor effect of osimertinib in a drug-refractory NSCLC patient-derived tumor xenograft model in NSG mice, without inducing notable adverse effects. These findings advocate the clinical evaluation of repurposing fexofenadine to overcome osimertinib resistance.

Antigen processing and presentation are fundamental for connecting innate and adaptive immune responses in combating cancers and infections. Reactive oxygen species (ROS), serving as second messengers in various physiological processes, play a vital role in modulating antigen processing and presentation. However, oxidative stress due to an imbalance characterized by excessive accumulation of ROS or inadequate antioxidant defenses can severely impair antigen-specific immune responses, contributing to the pathophysiology of multiple health conditions, notably including various cancers, cancer-associated infections and autoimmune diseases. This review comprehensively investigates the multifaceted effects of ROS on antigen processing and presentation, encompassing immunopeptide generation, the functionality of antigen-presentation machinery (APM), and the interactions of antigen-presenting cells and antigen-specific effector cells. It emphasizes the critical pathophysiological roles of oxidative stress in diseases such as cancers, cancer-associated infections and autoimmune diseases. Moreover, we delve into the therapeutic potential of targeting redox homeostasis to enhance antitumor immune responses. By illuminating the intricate interplay between ROS and immune functionality, this review provides an essential theoretical framework for developing innovative immunotherapy strategies aimed at restoring immune competency and improving clinical outcomes in patients with immune-related diseases.

Hepatocellular carcinoma (HCC) ranks third in global cancer-related mortality, with limited therapies for advanced stages. Retinol, the alcohol form of vitamin A, has long been associated with liver diseases. Plasma retinol levels have been inversely correlated with the risk and poor prognosis of HCC. In this study, transcriptome data analysis identified retinol metabolism as the seventh KEGG-dysregulated pathway in cirrhosis tissue, ascending to the top position in HCC tissue compared to normal tissue. Specifically, a consistent downregulation of ADH4 (alcohol dehydrogenase 4), the retinol dehydrogenase among human ADHs, was observed, which correlated with poor prognosis in HCC patients. In vivo experiments demonstrated that silencing ADH4 enhances liver fibrosis and the progression of HCC. Mechanistically, ADH4 elevated intracellular levels of RA (retinoic acid), a biologically active derivative of retinol. RA-activated retinoid receptors RARs/RXRs, leading to inhibition of the downstream Wnt/β-catenin pathway and thereby hindering HCC progression. In contrast, the knockdown of ADH4 in hepatocytes triggers apoptosis. Notably, additional results demonstrated that the combined treatment of RA and cisplatin achieved synergistic antitumor effects in a mouse HCC model. In summary, our research elucidates that ADH4-mediated RA production suppresses HCC growth, providing a theoretical foundation for HCC treatment.

Adenosine 5′-triphosphate (ATP) plays a crucial role in intracellular energetic metabolism and functions as a signal transducer in shaping the tumor microenvironment (TME). However, the understanding of the biological functions of adenosine phosphate signaling and its clinical relevance remains limited. Here, we deciphered the multi-omics dysregulation of 15 purinergic P2 receptors (P2Rs) and their clinical relevance. We revealed the presence of 5 ATP signaling subtypes in melanoma, with two distinct functional metaprograms—one metabolic and the other inflammatory. We developed an adenosine phosphate signaling model (APsig) that showed promising prognostic value in melanoma, as well as predictive efficacy of immunotherapy across 1068 tumor samples in 9 independent public cohorts. High APsig was associated with longer overall survival (OS) and improved response to tumor immunotherapy. Additionally, through single-cell and spatial transcriptomic analysis, we explored how APsig promotes antitumor immunity by activating myeloid lineage cells for antigen presentation. Our comprehensive characterization of P2R-mediated adenosine phosphate signaling at both bulk/single-cell and spatial transcriptomic levels highlights its potential as a promising target for developing novel anticancer agents, particularly in combination with immune checkpoint inhibitors.

The tumor microenvironment (TME) is a complex and dynamic ecosystem crucial for cancer development and progression. Within this intricate milieu, T-cells constitute a heterogeneous population and serve as a cornerstone of antitumor immunity. Notably, T-cells can rapidly transition across a wide spectrum of phenotypic and functional states within the disrupted TME. Despite the crucial role of T-cells in cancer immunity, a comprehensive understanding of their plasticity within the TME remains limited. In this review, we delve into the functional plasticity and spatial distribution of T-cells in response to diverse microenvironmental conditions. Additionally, we review the plasticity of T-cell functional states during conventional therapies, highlighting their potential to enhance or limit therapeutic outcomes. Finally, we propose innovative therapeutic approaches that leverage T-cell plasticity to enhance clinical efficacy by regulating the immune response within the TME. By providing insights into the dynamics of T-cell behavior, this review highlights the promising potential of targeting T-cell plasticity as an immuno-sensitizer to refine therapeutic strategies and overcome current challenges in cancer treatment.

Mitochondria, as the main site for aerobic respiration in cells, are indispensable participants in the reprogrammed metabolic activities of tumor cells. Mitochondrial ribosomal proteins (MRPs), essential components of the mitochondrial ribosome (mitoribosome), play a critical role in maintaining mitochondrial function and regulating oncogenic signaling. Their molecular mechanisms and biological functions make MRPs key regulators of tumorigenesis, drug resistance, and tumor immune escape. MRPs are abnormally expressed in various cancer types and are linked to the prognosis of cancer patients. However, a thorough grasp of the specific mechanisms and a holistic analysis of the relationship between MRPs and different cancers are lacking. This review highlights the specific regulatory roles of MRPs, including MRPS5, MRPS29, MRPL9, MRPL12, MRPL13, MRPL33, MRPL58, and MRPL59, in cancer. Additionally, we examine the potential of MRPs as prospective clinical biomarkers and discuss their relationship with clinical prognosis and treatment response. We further explore the underlying reasons for the diverse functions of MRPs, their implications in cellular signaling and tumor immunity, and consider the prospects for developing MRP inhibitors as therapeutic strategies. Our comprehensive analysis deepens the understanding of MRPs complex biological functions and emphasizes their promising potential as therapeutic targets in cancer treatment.

Phosphatases are increasingly recognized as critical regulators of cancer biology, with important roles in both tumor cells and the tumor immune microenvironment (TIME). These enzymes modulate intracellular signaling pathways that control tumor growth, immune evasion, and metastasis. Although phosphatases were once considered undruggable, recent advances have highlighted their therapeutic potential. Despite growing evidence, phosphatases remain underexplored as drug targets, with no approved therapies to date. This review presents an in-depth overview of phosphatase classification based on catalytic domain similarities and explores their diverse functions as tumor suppressors, oncogenic drivers, or context-dependent regulators. We describe how phosphatases such as PTPN6, PTPN22, and DUSPs regulate key pathways like RAS/MAPK and PI3K/AKT in both tumor and immune cells. Additionally, we discuss the role of phosphatases in shaping the tumor microenvironment through exosome secretion. This review highlights current therapeutic strategies, including small molecules and antibodies, and their synergistic effects with kinase inhibitors and immune checkpoint blockade. By summarizing recent advances, this paper underscores the need for deeper mechanistic insights into phosphatase function in cancer and immunity. Understanding these mechanisms will be key to unlocking their potential as novel therapeutic targets in oncology.