Navigating Tumor Microenvironment Barriers with Nanotherapeutic Strategies for Targeting Metastasis

Abstract Therapeutic strategy for efficiently targeting cancer cells needs an in‐depth understanding of the cellular and molecular interplay in the tumor microenvironment (TME). TME comprises heterogeneous cells clustered together to translate tumor initiation, migration, and proliferation. The TME mainly comprises proliferating tumor cells, stromal cells, blood vessels, lymphatic vessels, cancer‐associated fibroblasts (CAFs), extracellular matrix (ECM), and cancer stem cells (CSC). The heterogeneity and genetic evolution of metastatic tumors can substantially impact the clinical effectiveness of therapeutic agents. Therefore, the therapeutic strategy shall target TME of all metastatic stages. Since the advent of nanotechnology, smart drug delivery strategies are employed to deliver effective drug formulations directly into tumors, ensuring controlled and sustained therapeutic efficacy. The state‐of‐the‐art nano‐drug delivery systems are shown to have innocuous modes of action in targeting the metastatic players of TME. Therefore, this review provides insight into the mechanism of cancer metastasis involving invasion, intravasation, systemic transport of circulating tumor cells (CTCs), extravasation, metastatic colonization, and angiogenesis. Further, the novel perspectives associated with current nanotherapeutic strategies are highlighted on different stages of metastasis.