Cancer Biology & Medicine最新文献

As an emerging biomarker, tumor mutational burden (TMB) has attracted increasing attention from clinicians in predicting the efficacy of tumor immunotherapy. Currently, TMB is detected primarily by whole-exome sequencing or targeted panel sequencing on high-throughput sequencing platforms. However, the lack of uniformity in detection methods, threshold settings, and reporting formats, as well as the significant differences in TMB values among different cancer types, have hindered the standardized application of this biomarker in clinical practice. This consensus focuses on the definition, standardization of detection, clinical significance, and limitations of TMB, and provides consensus recommendations for the clinical application of TMB in real-world practice in China. This consensus is aimed at helping clinicians and laboratory personnel understand the clinical significance and testing standards of TMB, promoting more accurate interpretation of test results, and improving patient care.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Objective: Recent clinical evidence indicates that persistent reservoirs of SARS-CoV-2 in human brain tissue are associated with various neurologic symptoms. While brain tumors have unique vascular abnormalities and immunosuppressive environments, it is unclear whether SARS-CoV-2 can infect brain tumors.

Methods: Brain tumor samples were collected from a cohort of 72 COVID-19 patients during the SARS-CoV-2 BA.5 wave in Guangzhou. SARS-CoV-2 infection was confirmed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining. Immune cell infiltration within the tumor tissues was assessed using IHC. RNA-sequencing was performed to investigate virus-host interactions in the brain tumors.

Results: Brain tumor samples from 72 COVID-19 patients were examined and SARS-CoV-2 RNA was detected in 11% of the samples, which included samples from craniopharyngiomas, pituitary neuroendocrine tumors (PitNETs), meningiomas, and gliomas. SARS-CoV-2 infection was present in tumor and endothelial cells within these brain tumors. SARS-CoV-2-positive tumors had greater immune cell infiltration, particularly an increase in CD8⁺ T cells in gliomas and pituitary PitNETs, along with the activation of innate signaling pathways. The transcriptomic analysis revealed that activation of the complement cascade within tumors may drive changes in the immune microenvironment of SARS-CoV-2-positive tumors.

Conclusions: These findings provided evidence of SARS-CoV-2 infection in brain tumors and suggested a role in altering the tumor immunosuppressive microenvironment.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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.