Gut microbiota‐derived metabolites are key hubs connecting the gut microbiome and cancer progression, primarily by remodeling the tumor microenvironment and regulating key signaling pathways in cancer cells and multiple immune cells. The use of microbial metabolites in radiotherapy and chemotherapy mitigates the severe side effects from treatment and improves the efficacy of treatment. Immunotherapy combined with microbial metabolites effectively activates the immune system to kill tumors and overcomes drug resistance. Consequently, various novel strategies have been developed to modulate microbial metabolites. Manipulation of genes involved in microbial metabolism using synthetic biology approaches directly affects levels of microbial metabolites, while fecal microbial transplantation and phage strategies affect levels of microbial metabolites by altering the composition of the microbiome. However, some microbial metabolites harbor paradoxical functions depending on the context (e.g., type of cancer). Furthermore, the metabolic effects of microorganisms on certain anticancer drugs such as irinotecan and gemcitabine, render the drugs ineffective or exacerbate their adverse effects. Therefore, a personalized and comprehensive consideration of the patient's condition is required when employing microbial metabolites to treat cancer. The purpose of this review is to summarize the correlation between gut microbiota‐derived metabolites and cancer, and to provide fresh ideas for future scientific research.

Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.

The emergence of immunotherapy has profoundly changed the treatment model for triple-negative breast cancer (TNBC). But the heterogeneity of this disease resulted in significant differences in immunotherapy efficacy, and only some patients are able to benefit from this therapeutic modality. With the recent explosion in studies on the mechanism of cancer immunotherapy drug resistance, this article will focus on the processes of the immune response; summarize the immune evasion mechanisms in TNBC into three categories: loss of tumor-specific antigen, antigen presentation deficiency, and failure to initiate an immune response; together with the aberrant activation of a series of immune-critical signaling pathways, we will discuss how these activities jointly shape the immunosuppressive landscape within the tumor microenvironment. This review will attempt to elucidate the molecular mechanism of drug resistance in TNBC, identify potential targets that may assist in reversing drug resistance, and lay a foundation for research on identifying biomarkers for predicting immune efficacy and selection of breast cancer populations that may benefit from immunotherapy.

NRF2 is an important regulatory transcription factor involved in tumor immunity and tumorigenesis. In this study, we firstly identified that FKBP4/NR3C1 axis was a novel negative regulator of NRF2 in human breast cancer (BC) cells. The effect of FKBP4 appeared to be at protein level of NRF2 since it could not suppress the expression of NRF2 at mRNA level. Bioinformatics analysis and in vitro experiments further demonstrated that FKBP4 regulated NRF2 via regulating nuclear translocation of NR3C1. We then reported that naringenin, a flavonoid, widely distributed in citrus and tomato, could suppress autophagy and proliferation of BC cells through FKBP4/NR3C1/NRF2 signaling pathway in vitro and in vivo. Naringenin was also found to promote dendritic cell (DC) differentiation and maturation through FKBP4/NR3C1/NRF2 axis. Therefore, our study found that naringenin could induce inhibition of autophagy and cell proliferation in BC cells and enhance DC differentiation and maturation, at least in part, though regulation of FKBP4/NR3C1/NRF2 signaling pathway. Identification of FKBP4/NR3C1/NRF2 axis would provide insights for novel anti-tumor strategy against BC among tumor microenvironment.

Background: Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. Non-coding RNAs (ncRNAs) are enriched in exosomes, which participated in generation, progression, and resistance of BC. However, the mechanism underlying the chemoresistance and metastasis in BC cells mediated by the BC-derived exosomal ncRNAs remained to be elucidated. Methods: The effects of PTX-induced exosomal circBACH1 on BC cell function were assessed using RNA Binding Protein Immunoprecipitation (RIP), dual luciferase reporter gene, tube formation, CCK-8, and Western Blot assays. The circBACH1 and miR-217 expression levels were detected using quantitative real-time PCR (RT-qPCR) and Immunohistochemistry (IHC) assays in BC tissues and precancerous tissues of BC patients. Results: CircBACH1 expression was increased in paclitaxel-treated BC-derived exosomes (PTX-EXO) and BC tissue. PTX-EXO was shown to promote PTX-resistance and angiogenesis through upregulation circBACH1. Downregulation of circBACH1 improved PTX-sensitiveness by suppressing the cell viability, stemness, migration, and angiogenesis of BC cells. Moreover, we found that miR-217 interacted with circBACH1 and targeted GTPase-activating SH3 domain-binding protein 2 (G3BP2) in BC cells. CircBACH1 combined miR-217 cotransfection suppressed the expression of G3BP2 proteins compared with circBACH1 treatment in MCF-7 cells. In addition, downregulation of G3BP2 suppressed BC cell migration. Conclusions: These results demonstrated that PTX-induced exosomal circBACH1 promoted stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.

Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.