MedComm – Oncology最新文献

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.

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.

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.

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.

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.

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.

In their paper published in Cell [1], Baldwin et al. used advanced techniques such as single-cell RNA sequencing, field emission scanning electron microscopy (FESEM), and confocal microscopy to systematically investigate the process by which bone marrow stromal cells (BMSCs) transfer mitochondria to CD8⁺ T cells via tunneling nanotubes (TNTs). Through a series of experiments, they revealed how this process enhances T cell metabolic adaptability and antitumor efficacy, thus establishing mitochondrial transfer as an organelle transplantation strategy for significantly boosting T cell metabolic resilience and antitumor potential.

Adoptive T cell therapy (ACT) is a personalized immunotherapy; however, its efficacy against solid tumors is often limited because of the suppressive tumor microenvironment, which impairs T cell mitochondrial function, leading to T cell exhaustion and reduced antitumor immunity [2]. Recent research has demonstrated mitochondrial transfer across different cell types, which can repair damaged cells and in some cases, support tumor growth by providing mitochondria to tumor cells.

At present, tunneling nanotubes (TNTs) are recognized as a major pathway for mitochondrial transfer. These structures, supported by F-actin, span considerable distances between cells, facilitating the intercellular exchange of cytoplasmic materials and organelles [3]. However, whether mitochondrial transfer could restore mitochondrial function in exhausted T cells and present a new avenue for T cell–targeted solid tumor therapy remained unclear until Baldwin et al. provided crucial evidence supporting this model.

Within coculture systems, the researchers observed interactions between BMSCs and CD8⁺ T cells, with field emission scanning electron microscopy (FESEM) capturing the formation of nanotubes between the two cell types. These nanotubes created intercellular “bridges” that enabled the transfer of mitochondria and other organelles from BMSCs to T cells. Confocal imaging analysis revealed a significant increase in mtDNA content within CD8⁺ T cells (referred to as Mito⁺ T cells) that had received mitochondria, confirming the occurrence of mitochondrial transfer from BMSCs. Further mechanistic investigation using gene enrichment analysis and immunoprecipitation sequencing revealed that Talin 2 (TLN2) acted as a key mediator of mitochondrial transfer via TNTs from BMSCs to CD8⁺ T cells, highlighting its essential role in initiating nanotube formation in BMSCs and facilitating mitochondrial transfer (Figure 1).

To assess how mitochondrial transfer influences the metabolic performance of T cells, the researchers analyzed the oxygen consumption rate (OCR) of CD8⁺ T cells, focusing on parameters such as basal respiration and spare respiratory capacity. The results indicated that Mito⁺ T cells exhibited sign

A recent research article published by Lee et al. [1] in Cell revealed that transforming growth factor β (TGF-β) and rat sarcoma viral oncogene homolog (RAS) signaling, together trigger expression of epithelial-to-mesenchymal transition (EMT) and fibrogenic factors enhancing cancer metastasis through a precise and complex system. The authors elucidated that RAS-responsive element-binding protein 1 (RREB1)-mediated TGF-β-dependent fibrogenesis, and EMT come together to form a program to regulate cancer metastasis (Figure 1). This study enhances our understanding of the crosstalk between RAS and TGF-β in cancer metastasis, providing a potential therapeutic target.

RREB1, comprising 15 zinc finger (ZF) domains, is a critical transcription factor downstream of the RAS/mitogen-activated protein kinase (MAPK) signaling cascade, which plays a significant role in integration of RAS and TGF-β signaling pathways. TGF-β-activated small mother against decapentaplegic (SMAD) transcription factors are recruited by MAPK-activated RREB1 to Snail family transcriptional repressor (SNAIL). The recruitment of SMADs to SNAIL increases expression of SNAIL and triggers induction of developmental and fibrogenic EMT in carcinoma cells [2, 3]. Furthermore, RREB1-eukaryotic translation elongation factor 1A1 (eEF1A1)-3′ UTR axis enhances the translation of mitochondrial respiratory complex proteins encoded in nucleus and offers a novel therapeutic target for combating leukemia stem cells (LSCs) [4].

Cancer metastasis is the primary cause of patient mortality. During cancer metastasis, EMT is a crucial process in which epithelial cells lose their typical characteristics and acquire traits of mesenchymal cells, enhancing cell migration, invasion of surrounding tissues, and resistance to treatments. Su et al. [2] and Fontana et al. [5] revealed that the synergy between the TGF-β and RAS pathways trigger the EMT in fibrogenesis. Additionally, they identified RREB1, a RAS transcriptional effector, as an important cofactor of SMAD inducing EMT-transcription factors' (TFs) expression. Furthermore, in human acute myeloid leukemia (AML), a short variant of RREB1, known as RREB1S (1368 bp), enhances translation of nuclear-encoded mitochondrial genes mediated through its interaction with the translational factor eEF1A1, to maintain the characteristics of LSCs [4]. However, the subset of TGF-β mediated EMT-TFs regulated by RREB1 and the specific mechanism of RREB1-integrated RAS and TGF-β signaling transduction in cancer metastasis remains unknown.

Activated mutant-Kirsten RAS (KRAS) is a key driver mutation in lung adenocarcinoma (LUAD) accounting for one of the most common genetic subsets of human LUAD [1]. Single cell RNA-sequencing and immunofluorescence findings of metastasis samples isolated from KRAS-mutated patients with LUAD suggested that EMT-TFs and f