Cancer Biology & Medicine最新文献

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.

Copper 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.

Objective: We previously reported that endogenous Sprouty-related, EVH1 domain-containing protein 2 (SPRED2), an inhibitor of the Ras/Raf/ERK-MAPK pathway, controls hepatocellular carcinoma (HCC) cell stemness by downregulating the expression of pluripotency factors, such as Nanog, c-Myc, and KLF4, in an ERK-dependent fashion. However, the exact mechanisms by which SPRED2 regulates HCC cell stemness have not been established.

Methods: Three human HCC cell lines [HepG2 (parental and SPRED2-deficient), HLE, and Hep3B] were used. Cells were transfected to downregulate or overexpress proteins. Western blot and RT-qPCR were used to evaluate the level of protein and mRNA expression. Co-immunoprecipitation and ChIP-qPCR were used to examine protein-protein interactions and the activation of gene transcription. Clinical HCC tissues were also used to validate in vitro data.

Results: KLF4 was identified as the major pluripotency factor responsible for SPRED2-mediated downregulation of HCC cell stemness and KLF4 expression was regulated by miR-506-3p. SPRED2 formed a protein complex with the tumor suppressor (p53) and upregulated miR-506 gene transcription by binding to the promoter region, resulting in subsequent downregulation of KLF4 mRNA expression. There was a negative correlation between KLF4 expression and miR-506-3p and a positive correlation between miR-506-3p expression and SPRED2 in human HCC samples, highlighting the relevance of the study findings.

Conclusions: The current study revealed a novel SPRED2/p53/miR-506-3p/KLF4 axis through which SPRED2 contributes to the suppression of HCC cell stemness and provides a potential new target to prevent HCC progression.

Objective: This study aimed to develop and validate a temporal radiomics model based on pre- and post-treatment CT scans for the preoperative prediction of pathologic complete response (pCR) in patients with resectable non-small cell lung cancer (NSCLC) undergoing neoadjuvant chemoimmunotherapy (NCI).

Methods: Data from 263 patients with resectable NSCLC who underwent NCI followed by curative surgery and had both pre- and post-treatment CT scans were retrospectively collected. Patients from one hospital were randomly divided into training and internal test sets at a 7:3 ratio, while patients from two other hospitals served as the external test set. Radiomics features were extracted from the CT scans at both timepoints and delta features capturing the temporal changes were calculated. Radiomics models based on different features were developed using the least absolute shrinkage and selection operator for feature selection, followed by logistic regression. Model performance was evaluated using the area under the curve (AUC).

Results: The radiomics model based on delta features yielded AUCs of 0.85, 0.76, and 0.72 in the training, internal test, and external test sets, respectively, which were superior to the radiomics models based on pre-treatment features (0.74, 0.66, and 0.62, respectively) and post-treatment features (0.80, 0.76, and 0.65, respectively). By integrating the optimal features from all three feature sources, the combined model achieved further improvements in performance, with AUCs of 0.89, 0.85, and 0.78, respectively, across the three sets.

Conclusions: A CT-based radiomics model incorporating temporal features from pre- and post-treatment scans shows favorable performance for the non-invasive preoperative estimation of pCR to NCI in patients with NSCLC.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.