基于纳米药物调控肿瘤成纤维样细胞用于肿瘤治疗的研究进展

Tumor tissues have a complex microenvironment containing various cellular and non-cellular components. Cancer-associated fibroblasts (CAFs) are the largest population in the stroma. CAFs can originate from many cell types, including native fibroblasts, stellate cells, epithelial cells, endothelial cells, and mesenchymal stem cells. We think the more precise description of CAFs is “tumor fibroblast-like cells” (TFLCs). TFLCs play pivotal roles in shaping the tumor microenvironment as the primary stromal cells through secreting various growth factors and extracellular matrix. For example, TFLCs secret vascular endothelial growth factor (VEGF) to regulate tumor angiogenesis, CXCL12 to upregulate anti-apoptotic proteins like Bcl-2 and survivin expression in tumor cells. TFLCs also establish physiological barriers within tumor tissues. For instance, TFLCs promote fabricating tumor extracellular matrix by secreting abundant collagens and fibronectin, which hinders the infiltration of immune cells and the penetration of anti-tumor drugs, and therefore impeding the efficacy of chemotherapy and immunotherapy. Consequently, modulating TFLCs can contribute to effectively suppressing tumor development and improving treatment outcomes. Due to the abundant distribution of TFLCs around tumor blood vessels, nanomedicines may first come into contact with TFLCs when they permeate from tumor blood vessels. Therefore, this provides relatively convenient conditions for utilizing nanomedicines to regulate TFLCs. The rational design of nanomedicines enables the targeted delivery of therapeutic agents to TFLCs, facilitating the modulation of TFLC functions at the genetic and/or molecular levels. Meanwhile, the phenotype, genes and protein levels of TFLCs could be changed after treatment, which may also provide new targets for nanomedicines. In this review, we give a concise overview of the origins and functions of TFLCs, and we focus on highlighting recent research progress on using nanomedicines to regulate TFLCs, such as loading chemotherapy drugs to directly deplete TFLCs, loading anti-fibrosis drugs to modulate TFLC function, and employing antibodies or nucleic acid drugs to precisely regulate signaling pathways in TFLCs. All these strategies prove that regulating TFLCs can enhance the efficacy of cancer treatment. To further develop this field, we need to pay more attention to the subtypes of TFLCs, especially the subtype population and signaling pathway changes of TFLCs before and after the treatments (chemotherapy, radiotherapy and/or immunotherapy). Since TFLCs are the largest stromal cell population in the tumor microenvironment, we may utilize TFLCs as a factory to produce drugs or antigens by using gene editing techniques to enhance the therapeutic efficacy. Overall, this review can provide feasible references for improving the treatment of solid tumors through regulating the tumor microenvironment.