Cancer Cell International最新文献

Non-small cell lung cancer (NSCLC) is currently the most prevalent malignancy worldwide, and its therapeutic resistance poses an enormous challenge to current therapeutic efforts. As the most common internal modification of RNA molecules, n6-methyladenosine (m6A) affects RNA structure and function and regulates gene expression. It is widely acknowledged that this modification contributes to progression and resistance to drug therapy in NSCLC. Because tumors exhibit heterogeneous characteristics, the functional expression of m6A-modifying enzymes and the molecular mechanisms and downstream pathways they regulate exhibit distinct phenotypic characteristics. By precisely controlling the methylation process, understanding the specific regulatory mechanisms involved in m6A modification may result in more effective treatments for NSCLC progression and drug resistance. This review summarizes recent functional analyses of m6A modifications in NSCLC, focusing on their impact on therapeutic responses via modulation of specific gene expression levels. Furthermore, we examined the potential of m6A modifications as therapeutic interventions and predictive biomarkers for drug resistance, aiming to enable individualized and precise therapeutic strategies to treat NSCLC.

In recent years, RNA modifications have been shown to play a key role in regulating immune cell functions, reshaping the tumor immune microenvironment (TIME), mediating immune escape, and influencing the efficacy of immunotherapy. These processes are central to the field of epitranscriptomics. Researchers have discovered various RNA modifications, such as N6-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N1-methyladenosine (m¹A), N7-methylguanosine (m⁷G), and N4-acetylcytosine (ac⁴C), that dynamically regulate the development, differentiation, activation, and functional state of immune cells through the " writers-readers-erasers " system-a set of enzymes that add, recognize, and remove these modifications-thus contributing to the formation and evolution of the TIME. Furthermore, RNA modification enzymes can serve as predictive markers of general immune responses and are also closely linked to responses to immunotherapy. Accordingly, they have become potential targets for combination therapies. As RNA modification detection technologies advance, researchers are uncovering the spatial heterogeneity and cell-specific regulatory mechanisms of RNA modifications in tumor immunity, which provides new strategies for targeted immunotherapy. However, the regulatory mechanisms of certain RNA modifications on specific immune cells remain unclear, and how to translate research findings into clinical applications also requires further exploration.

Gastric cancer (GC) is one of the most common and deadly types of cancer worldwide. In China, it is the most frequently occurring digestive tract tumour. Compared to traditional chemotherapeutic regimens centred on platinum and fluorouracil, immunotherapy has become one of the most important treatments for gastric cancer. Immune checkpoint inhibitors (ICIs) have the potential to benefit patients in the long term, but their development is limited by a high rate of resistance. To improve the efficacy of ICIs, it is important to understand the resistance mechanism in GC patients. In this paper, we review the resistance mechanisms of ICI in gastric cancer patients from four aspects: tumour immunity, immunosuppressed TME, tumour cells, and microbial populations.Additionally, we discuss new strategies and ideas to address ICI resistance in gastric cancer patients.

Melanoma is a highly malignant tumor. In the past, treatment options like chemotherapy were of limited benefit, and its prognosis, particularly in the advanced stage, was poor. The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape for melanoma and significantly improved patient survival. However, the efficacy of ICIs monotherapy remains limited, with only a small proportion of cancer patients benefiting. It has been proposed that oncolytic viruses (OVs) can significantly increase the density of CD8 + T-cells in tumors by modulating the tumor microenvironment from "cold" to "hot", and this change can synergistically activate anti-tumor immunity in conjunction with ICIs, thus improving the response rate of ICIs therapy. This change can synergize with ICIs to activate the body's anti-tumor immunity, thus improving the response rate of ICIs. However, there are still some unanswered questions, such as whether the combination will increase the incidence of adverse reactions. This review systematically combed the available clinical trial data to assess the feasibility and clinical application value of combining ICIs with OVs in the treatment of melanoma, as well as summarized the occurrence of adverse reactions in the clinical studies, analyzed their characteristics, and made management recommendations. Our review constructs a new theoretical framework for melanoma treatment, focusing on directions such as efficacy and adverse effects to provide practical guidance for clinical practice.

Background: Lenvatinib resistance is a major clinical challenge in advanced hepatocellular carcinoma (HCC). While ferroptosis has emerged as a promising target to overcome therapy resistance, the mechanistic link between ferroptosis and lenvatinib resistance in HCC remains incompletely understood.

Methods: We analyzed clinical data from TCGA-LIHC and performed functional assays in two HCC cell lines. RNA antisense purification sequencing (RAP-seq) was used to identify downstream targets, and the mechanisms were validated by dual-luciferase reporter assays and Western blotting. Ferroptosis was assessed by measuring lipid reactive oxygen species (lipid ROS) and labile iron levels. Therapeutic efficacy was evaluated both in vitro and in vivo.

Results: MIR4435-2HG was upregulated in HCC and associated with poorer overall survival. It promoted malignant phenotypes and was further upregulated in lenvatinib-resistant cell lines. Mechanistically, MIR4435-2HG functioned as a competing endogenous RNA (ceRNA) by sponging miR-29c-3p, resulting in upregulation of FSP1. This axis suppressed ferroptosis, thereby conferring lenvatinib resistance. Knockdown of MIR4435-2HG or inhibition of FSP1 synergized with lenvatinib to induce ferroptosis and overcome resistance. The combination strategy significantly suppressed tumor growth in vivo without apparent systemic toxicity.

Conclusion: Our findings identify a previously uncharacterized MIR4435-2HG/miR-29c-3p/FSP1 axis that promotes lenvatinib resistance by inhibiting ferroptosis, highlighting that targeting this axis may provide a mechanistic basis and preclinical rationale for overcoming lenvatinib resistance in HCC.

Background: Previous research suggests that tumor-associated macrophages (TAMs) influence the cisplatin (DDP) tolerance of gastric cancer (GC) cells via the secretion of microRNA-containing exosomes. This study aims to investigate the role of exosomal miR-668-3p from M2 macrophages in modulating DDP resistance, using both in vitro and in vivo models to provide a comprehensive analysis.

Materials and methods: The expression profiles of DDP-resistant GC tissues were assessed through microarray, while immunofluorescence confirmed the uptake of these exosomes by GC cells. The role of miR-668-3p in regulating DDP resistance was explored using CCK8 assays, colony formation, EDU incorporation, and Western blotting. The interaction between miR-668-3p and ETS1 was validated through RIP and RNA pull-down assays. Furthermore, the regulatory role of the miR-668-3p/ETS1/EGFR axis in autophagy and DDP resistance was examined in GC cell lines and a tumor xenograft model.

Results: miR-668-3p was significantly upregulated in DDP-resistant GC tissues. Exosomes originating from M2 macrophages transfer miR-668-3p to GC cells, enhancing their DDP resistance. Additionally, miR-668-3p was found to bind to ETS1 mRNA, leading to its suppression and a consequent decrease in EGFR expression. This reduction in EGFR expression was closely linked to the activation of autophagy, further augmenting DDP resistance in GC cells.

Conclusion: M2 macrophage-derived exosomal miR-668-3p promotes DDP resistance in GC cells by targeting the ETS1/EGFR axis, thereby activating the autophagy pathway. Future research should focus on developing targeted inhibition strategies for miR-668-3p to effectively reverse DDP resistance in GC cells, optimizing its potential for clinical application.

Background: Accurate human epidermal growth factor 2 (HER2) assessment is critical for guiding breast cancer (BC) treatment. Circulating tumor cells (CTCs), which detach from the primary or secondary tumors and circulate through the bloodstream, can colonize distant sites to form metastases. Previous studies have demonstrated the clinical validity of CTCs as prognostic biomarkers in metastatic breast cancer (mBC). Liquid biopsy testing offers a non-invasive alternative for real-time evaluation of HER2 expression on CTCs, overcoming limitations of repeated histological sampling.

Methods: This study employed a pipeline combining EpCAM-independent enrichment with Parsortix^® and immunofluorescence (IF)-based HER2 characterization to assess HER2 expression in patient-derived CTCs from sixteen patients with mBC and compared it to the FDA-approved CellSearch^® system and to the HER2 tissue status. CTC detection rates, median CTC counts per 7.5 mL blood, and the fraction of HER2-positive CTCs per sample were determined, and CTC versus tissue status was compared to assess concordance.

Results: The two methods had a strong positive correlation in CTC counts, with the label-free workflow showing a higher CTC detection (100% versus 77% samples with ≥ 1 CTC). Median total CTC counts per 7.5 mL blood were 16.5 (range 3-65) for Parsortix^® and 3 (range 1-245) for CellSearch^®. Despite a different HER2-positive CTC detection rate (38% versus 11% using Parsortix^® and CellSearch^®, respectively), both methods showed concordance with the tissue, with the distribution of HER2-positive CTCs reflecting the HER2 status of the biopsy. Patients with HER2-positive mBC showed a higher proportion of HER2-positive CTCs compared to patients with HER2-negative tissue both with Parsortix (55% versus 33%) and with CellSearch (61% versus 1%). No differences in HER2-positive CTC distribution were observed between patients with HER2-low and HER2-zero tumors.

Conclusion: These results support the clinical utility of HER2 assessment on CTCs with both workflows and highlight the potential diagnostic value of label-free CTC enrichment combined with HER2 quantification. Further studies in larger cohorts should be conducted to validate our findings and investigate the clinical relevance of HER2-positive CTCs detected with the developed pipeline, particularly in the context of anti-HER2 therapies.