Phytonanomedicine: An Assessment of Therapeutic Relevance in Cancer Through Targeting Cancer‐Associated Fibroblast in Tumor Microenvironment

Tumors progress within a complex intricate territory consisting of tumorigenic cancer cells with heterogeneous stromal, cellular and non-cellular soluble constituents. The tumor microenvironment (TME) continuously crosstalks with the tumor cells, which helps the tumor cells in achieving different malignant phenotypes and later aids in tumor initiation, progression, and metastasis. Cancer associated fibroblasts (CAFs) constitute a chief component of the TME that is often corroborated with unfavorable disease outcomes, therapy resistance and distant metastasis. CAFs are essential components of TME which facilitate intricate communication between cancer cells, release numerous regulatory factors, thereby aiding tumor growth, synthesize and remodel the extracellular matrix providing drug resistance and regulating immune cell infiltration into TME. Thus, inspecting new therapeutic approaches for targeting CAFs may reverse the current landscape of cancer therapy. Recently, several phytochemicals, such as curcumin, resveratrol, quercetin, silibinin and others, have been studied to demonstrate several regulatory effects on TME. These phytochemicals often target different oncogenic signaling pathways orchestrated within TME components like cancer cells, CAFs, immune cells, cancer stem cells, and endothelial cells crucial for tumor development and progression. Several research findings have demonstrated that different anti-fibrotic phytochemicals in combination with chemotherapeutics have shown better therapeutic efficacy by modulating CAFs in TME. However, despite promising preclinical outcomes, challenges such as poor bioavailability, low solubility, hydrophobicity and obscure target specificity restrict their therapeutic applications in the clinic. There has been acontinually increasing interest to formulate phytonanomedicine, the integration of phytochemicals and nanotechnology using various nanocarriers like liposomes, micelles, and nanoemulsions to improve their bioavailability and target specificity, thereby maximizing the therapeutic potential. In the present review, we have highlighted the mechanistic pathways through which phytonanomedicine interacts with CAFs, addresses current challenges in clinical translation, and suggests future research directions to optimize the use of natural-product-based nanotherapeutics in anti-CAF strategies for cancer treatment.