Objective. Immunotherapy is a promising breast cancer treatment. Nonetheless, tumor heterogeneity and the interaction between immune cells in the tumor microenvironment limit its effectiveness. Formononetin—extracted from the Chinese medicinal plant Astragalus membranaceus—can inhibit tumor growth, induce apoptosis and angiogenesis, and reverse multidrug resistance. However, its efficacy and mechanism of action on the immune cells in breast cancer remain unclear. Here, we screened immune-related genes of breast cancer to determine the potential of formononetin as a therapeutic. Methods. GSE103512 and GSE139038 breast cancer microarray data and immune-related gene data were obtained from the GEO and ImmPort databases, respectively, to analyze the differentially expressed immune-related genes (IRGs) in breast cancer tissues compared with normal breast tissues. Protein-protein interaction (PPI) analysis was performed using the STRING database to screen differentially expressed IRGs based on the topological parameters. The Kaplan–Meier test was applied to detect differentially expressed IRGs associated with breast cancer survival, and the interaction of formononetin with differentially expressed IRGs was analyzed using molecular docking. Finally, the relationship between differentially expressed IRGs and breast cancer immune cell infiltration was analyzed using the TIMER2.0 database. Results. A total of 29 differentially expressed IRGs of breast cancer were screened through GEO and ImmPort databases and 10 key differentially expressed IRGs based on the topological parameters from the PPI network. Among these, CXCL12, ESR1, IGF1, and FOS were associated with breast cancer survival. Furthermore, IGF1, ESR1, and CXCL12 were found to have stable binding sites for formononetin. These genes were associated with substantial immune cell infiltration in breast cancer tissues. Conclusion. In conclusion, formononetin may exert antitumor effects by acting on CXCL12, ESR1, and IGF1 and may have a potential synergistic effect with immune checkpoint inhibitors.
Immunotherapy has revolutionized the landscape in clinical tumor therapy, although the response rates in "cold" tumors are relatively low owing to the complex tumor microenvironment (TME). Cyclic guanosine monophosphateadenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway-inducing agents can reprogram the TME; however, their applications remain underutilized. Herein, we engineered a facile manganese-based metal−organic framework (Mn-MOF) encapsulating polyphyllin I (PPI) and coated it with red blood cell (RBC) membranes (RBC@Mn-MOF/PPI) that enhanced the cGAS/ STING-mediated antitumor immunity. RBC@Mn-MOF/PPI was engineered by camouflaging it with a biomimetic RBC membrane for prolonged blood circulation and immune escape, which was also extended with TME-sensitive properties for triggering the release of PPI and Mn 2+ to remodel the suppressive TME and augment antitumor immune responses. Furthermore, RBC@Mn-MOF/PPI helped transform cold tumors into "hot" ones by activating immune cells, as evidenced via dendritic cell maturation, cytotoxic T lymphocyte infiltration, and natural killer cell recruitment, thereby targeting primary and abscopal tumors and lung metastatic nodules. Therefore, our engineered nanosystem represents a novel strategy to transform immunologically "cold" tumors into "hot" ones by activating the cGAS/STING pathway, thereby addressing the major challenges associated with immunotherapy.
Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of lung cancer, especially in the first-line treatment of advanced NSCLC, and EGFR-TKIs monotherapy has achieved better efficacy and tolerability compared with standard chemotherapy. However, acquired resistance to EGFR-TKIs and associated adverse events pose a significant obstacle to targeted lung cancer therapy. Therefore, there is an urgent need to seek effective interventions to overcome these limitations. Natural medicines have shown potential therapeutic advantages in reversing acquired resistance to EGFR-TKIs and reducing adverse events, bringing new options and directions for EGFR-TKIs combination therapy. In this paper, we systematically demonstrated the resistance mechanism of EGFR-TKIs, the clinical strategy of each generation of EGFR-TKIs in the synergistic treatment of NSCLC, the treatment-related adverse events of EGFR-TKIs, and the potential role of traditional Chinese medicine in overcoming the resistance and adverse reactions of EGFR-TKIs. Herbs and active compounds have the potential to act synergistically through multiple pathways and multiple mechanisms of overall regulation, combined with targeted therapy, and are expected to be an innovative model for NSCLC treatment.
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