Latest ArticlesCopper ions are essential for cellular function but can induce cytotoxic effects when dysregulated. This review explores the multifaceted role of copper in cancer metabolism with a focus on the novel concept of cuproptosis, a regulated form of cell death triggered by copper accumulation. The mechanisms underlying copper homeostasis are detailed, including dietary absorption, systemic distribution, and intracellular utilization. Key transporters, such as copper transporter 1 (CTR1) and ATPase copper transporting alpha/b (ATP7A/B), are highlighted. Cancer cells often exhibit elevated copper levels, supporting proliferation and metastasis through pro-tumorigenic pathways. Recent studies have shown that disrupting copper homeostasis can induce cuproptosis, which is characterized by the aggregation of lipoylated mitochondrial proteins and disruption of iron-sulfur cluster biogenesis. Advances in copper-based nanotechnology have enabled targeted delivery of copper to tumors, enhancing therapeutic efficacy through synergistic effects with reactive oxygen species (ROS) generation and immunomodulation. However, the hypoxic tumor microenvironment poses significant challenges by upregulating copper-sequestering proteins and downregulating key cuproptosis mediators. Future directions include integrating multi-omics approaches to identify novel therapeutic targets and developing combination therapies to overcome hypoxia-induced resistance. This review provides a comprehensive overview of copper metabolism in cancer, emphasizing the potential of cuproptosis induction as a powerful strategy for oncologic intervention.
In recent years the crucial role of CD4+ T cells in tumor immunomodulation has garnered increasing recognition. While conventional cancer immunotherapy research has predominantly focused on the cytotoxic function of CD8+ T cells, emerging evidence has now shown that CD4+ T cells enhance antitumor immunity by delivering co-stimulatory signals, secreting cytokines, and promoting cytotoxic T lymphocyte (CTL) activation and display unique immunoregulatory capabilities through direct tumor cell killing or remodeling of the tumor microenvironment. The high heterogeneity and functional plasticity of CD4+ T cell subsets significantly influence clinical responses to immunotherapy with underlying mechanisms involving multi-level regulatory networks, including epigenetic modulation and metabolic reprogramming. Deciphering the functional heterogeneity of CD4+ T cells and the interactions with the tumor microenvironment will provide essential mechanistic insights for next-generation immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) therapies, thereby advancing personalized treatment paradigms.
Anti-programmed cell death protein 1 (PD-1) or its ligand (PD-L1) are immune checkpoint inhibitors (ICIs) that have revolutionized cancer therapy. However, the efficacy of anti-PD-1 and anti-PD-L1 is limited by resistance and inter-individual variability. In recent years increasing evidence has highlighted the pivotal role of the gut microbiota in modulating the response to PD-1/PD-L1 immunotherapy. Extensive preclinical studies have demonstrated that commensal microbes can increase the efficacy of PD-1/PD-L1 blockade through multiple mechanisms, including the production of metabolites, such as short-chain fatty acids (SCFAs), tryptophan derivatives, and extracellular polysaccharides that remodel the tumor microenvironment, as well as the activation of immune pathways involving dendritic cells, CD8⁺ T cells, and M1 macrophages to increase antitumor immunity. Moreover, clinical studies have shown that fecal microbiota transplantation (FMT) and targeted probiotic interventions show promise for improving the response to PD-1/PD-L1 therapy, while reducing the risk of immune-related adverse events (irAEs). This review systematically explores the multifaceted regulatory roles of the commensal microbiota in PD-1/PD-L1 therapy and examines the preclinical prospects of microbiota-based personalized immunotherapeutic strategies. The integration of multiomics technologies, synthetic biology, and precise microbiota interventions may further optimize PD-1/PD-L1 immunotherapy and offer novel insights into antitumor immune modulation.
This study aimed to determine the role and mechanism underlying migration and invasion inhibitory protein (MIIP) modulation in M2 macrophages within the tumor microenvironment and the potential of targeting the MIIP– stimulator of interferon genes (STING) pathway in colorectal cancer (CRC) therapy.
MIIP expression was analyzed for associations with the STING pathway and M2 macrophage infiltration using public datasets and clinical CRC samples. CRC cells were genetically modified using lentiviral vectors to overexpress or silence MIIP and STING. The interactions of genetically modified CRC cells with macrophages were studied in co-culture systems. Techniques, including immunofluorescence staining, RT-qPCR, western blot, ELISA, flow cytometry, and Transwell migration and invasion assays, were used to evaluate the crosstalk between CRC cells and macrophages. An orthotopic mouse CRC model was developed to study the effects of MIIP on M2 macrophage polarization and tumor metastasis through the STING–NFκB2–IL10 axis. The therapeutic significance of a STING antagonist was also assessed in vivo.
Analyses of The Cancer Genome Atlas (TCGA) cohort and our CRC cohort revealed low MIIP expression is associated with STING pathway activation, increased M2 macrophage infiltration, and poor clinical outcomes. The results of functional experiments demonstrated that MIIP inhibits IL10 production via the STING–TRAF3–NFκB2 axis in CRC cells, suppressing M2 macrophage polarization in co-culture systems. Conversely, M2 macrophages promoted CRC cell migration and invasion in an IL10-dependent manner. In vitro and in vivo studies confirmed that the MIIP-mediated feedback loop between CRC cells and macrophages depends on the STING–NFκB2–IL10 axis. Furthermore, inhibition of STING expression in a mouse model reduced M2 macrophage polarization and tumor metastasis.
This study established MIIP as a crucial regulator of macrophage polarization in the CRC tumor microenvironment, providing new insights into the role in suppressing CRC progression and immune–tumor crosstalk. These findings highlight the potential of targeting the STING pathway as a therapeutic strategy for CRC patients who respond poorly to immune checkpoint inhibitors.
Breast cancer is the most common malignancy in women and is characterized by a high recurrence rate that severely impacts patient survival. Regulatory T cells (Tregs) in the tumor microenvironment (TME) promote immune evasion and metastasis, increasing recurrence risk. This study determined how the epigenetic regulators, DNMT3A and METTL7A, modulate Treg infiltration via the DDR1/STAT3/CXCL5 axis and influence breast cancer recurrence and prognosis.
RNA sequencing (RNA-seq) was used to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Machine learning algorithms, including least absolute shrinkage and selection operator (LASSO), supported vector machine-recursive feature elimination (SVM-RFE) and ElasticNet identified DDR1 as a key gene. Validation included RT-qPCR, western blot, MSP, MeRIP-qPCR, and Co-IP to assess epigenetic regulation. Functional assays (CCK-8, Transwell, and Treg differentiation/chemotaxis) and xenograft models evaluated the role of DDR1 in tumor progression and recurrence.
DNMT3A upregulated DDR1 via DNA methylation, while METTL7A enhanced DDR1 mRNA stability via m6A modification. Co-regulation activated the DDR1/STAT3/CXCL5 axis, which boosted cancer cell proliferation, migration, and invasion. CXCL5 secretion increased Treg infiltration and accelerated tumor growth in vivo. DDR1 silencing reversed these effects, confirming that DDR1 has a pivotal role in breast cancer recurrence.
DNMT3A and METTL7A were shown to cooperatively regulate DDR1 via DNA/m6A methylation, which drives Treg-mediated immune suppression and recurrence. This study provided novel insights and therapeutic targets for breast cancer prognosis and treatment.
Clinical use of stimulator of interferon genes (STING) agonists has challenges due to poor responsiveness and variable efficacy. Therefore, identifying tumor types that are sensitive to these agents and clarifying the underlying mechanisms are essential.
In vitro screening was performed to identify tumor types that are sensitive to STING agonists. The non-nucleotide agonist, SR-717, and the macrocyclic agonist, E7766, were compared for efficacy. Complementary in vivo and in vitro studies, including gene-knockout models, HMGN2-knockout Neuro-2A and CT-2A cells apoptosis assays, and murine tumor models, were then performed. These experiments focused on the mechanism by which SR-717 mediates antitumor effects and emphasized the role of STING signaling-induced high-mobility group nucleosome-binding protein 2 (HMGN2). In addition, the potential of HMGN2 as a prognostic biomarker was assessed.
Neuroblastomas and glioblastomas, two nervous system tumors, were shown to be sensitive to STING agonists. SR-717 exhibited greater antitumor efficacy compared to E7766. Mechanistic studies indicated that STING agonists promote apoptosis through activation of the intrinsic STING-signal transducer and activator of transcription 1 (STAT1)-HMGN2 axis within tumor cells. Ectopic expression of HMGN2 in melanoma cells, which naturally lack HMGN2, led to significant apoptosis. Furthermore, analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases revealed positive correlation between elevated HMGN2 expression and patient survival, supporting the utility of HMGN2 as a prognostic biomarker.
This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766. In addition, HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.
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