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Currently, clinically used antitumor nanomedicine is usually insufficient to eradicate malignancies, due to the tumor stroma exerting therapeutic resistance and physical barriers for proper drug delivery. As the most abundant cells in the tumor stroma, cancer-associated fibroblasts (CAFs) produce a critical tumor-promoting effect and barriers preventing the physical delivery of nanomedicines through secreting pro-tumorigenic cytokines, increasing solid tumor pressure and interstitial fluid pressure (IFP), and nonspecific internalization. Therefore, beyond treatment centered on cancer cells, researchers are focusing on targeting CAFs to fight stromal-rich tumors. In recent years, a series of novel nano delivery systems have been developed based on specific CAF-targeted ligands and advanced biofunctional materials. On the one hand, CAF-targeted nano delivery systems inhibit the pro-tumor signaling pathway between CAFs and cancer cells to reverse tumorigenesis, immunosuppression, or drug resistance in the tumor microenvironment, thus improving the sensitivity to antitumor treatments. On the other hand, nanostrategies acting on CAFs profoundly contribute to increasing the deep penetration of antitumor drugs through the decrease of solid pressure, IFP, and dense extracellular matrix generation related to the resistance to intratumoral diffusion. In this review, we first introduce the biological mechanisms of CAFs that interfere with nanotherapy. The state-of-the-art passive and active strategies of nano delivery systems targeting CAFs are then summarized, focusing on the therapeutic mechanism involved and the rational design of nano delivery systems. Additionally, the challenges of CAF-targeted nanotherapy are discussed from the perspectives of developing efficient nano delivery systems and potential clinical use.

Currently, the chemotherapy drugs-loaded thermosensitive liposomes have not shown an over standard of clinical effects compared to preclinical trials. In addition to the limiting factors of clinical trial design and heating device, abnormal angiogenesis in desmoplastic tumor is a key factor for unexpected clinical efficacy. Malformed tumor vasculature may result in reduced vascular transport and the heterogeneous distribution of thermosensitive liposomes in tumor. Here, we report an anti-angiogenesis strategy through hypoxia-inducible factors (HIF)-1α-vascular endothelial growth factor (VEGF) axis based on icaritin and coix seed oil dual loaded multicomponent thermosensitive lipid complexes (IC-ML). IC-ML could downregulate the HIF-1α expression in HepG2 cells with a synergetic antitumor effect. In addition, HepG2 + LX-2 cells co-cultured 3D tumor spheres administered IC-ML showed the strongest penetration and inhibition of growth. Accordingly, IC-ML displayed improved tumor penetration and superior synergistic antitumor efficacy with HIF-1α-VEGF downregulation in vivo under mild hyperthermia. The improvement of antitumor efficacy of IC-ML comes from the anti-angiogenesis strategy and comprehensive tumor microenvironment remodeling, including depletion of cancer-associated fibroblasts as well as inhibition of M2-type tumor associated macrophage infiltration in desmoplastic tumor. This study proposes a novel multicomponent synergistic antitumor strategy to improve the therapeutic potential of thermosensitive lipid complexes for hepatocellular carcinoma.