Tumor microenvironment and cancer metastasis: molecular mechanisms and therapeutic implications

Abstract

The tumor microenvironment (TME) plays a crucial role in cancer development and metastasis. This review summarizes the current research on how the TME promotes metastasis through molecular pathways, focusing on key components, such as cancer-associated fibroblasts, immune cells, endothelial cells, cytokines, and the extracellular matrix. Significant findings have highlighted that alterations in cellular communication within the TME enable tumor cells to evade immune surveillance, survive, and invade other tissues. This review highlights the roles of TGF-β and VEGF signaling in promoting angiogenesis and extracellular matrix remodeling, which facilitate metastasis. Additionally, we explored how metabolic reprogramming of tumor and stromal cells, influenced by nutrient availability in the TME, drives cancer progression. This study also evaluated the therapeutic strategies targeting these interactions to disrupt metastasis. By providing a multidisciplinary perspective, this study suggests that understanding the molecular basis of the TME can lead to more effective cancer therapies and identify potential avenues for future research. Future research on the TME should prioritize unraveling the molecular and cellular interactions within this complex environment, which could lead to novel therapeutic strategies and personalized cancer treatments. Moreover, advancements in technologies such as single-cell analysis, spatial transcriptomics, and epigenetic profiling offer promising avenues for identifying new therapeutic targets and improving the efficacy of immunotherapies, particularly in the context of metastasis.

Keywords: cancer metastasis; cellular microenvironment; molecular mechanisms; signal transduction; tumor microenvironment.

FIGURE 1

Schematic therapeutic targeting and methodological advances in TME research This figure illustrates various therapeutic strategies and methodological advances in the study of the TME, with a particular focus on the key areas of intervention and research tools used to analyze its dynamics. The schematic highlights the integration of therapeutic approaches targeting cancer-associated fibroblasts, immune cells, and angiogenesis, as well as the application of advanced methodologies such as single-cell RNA sequencing, spatial omics, and live imaging techniques.

FIGURE 2

Key Signaling Pathways in TME-Mediated Cancer Metastasis. (A) CAFs, immune, and endothelial cells are surrounded by ECM and signals promoting tumor spread. (B) Immune cells in the TME can be manipulated to support tumor growth. Tumor-associated macrophages (TAMs) aid tumors by suppressing immune responses and enhancing angiogenesis through signals like VEGF. (C) The metalloproteinases (MMPs) enzymes break down ECM proteins, clearing a path for the cancer to spread. (D) Tumor cells can escape immune attack by engaging immune checkpoints to turn off immune responses. (E) The TME’s signaling networks involve interactions among various cell types. Tumor cells and CAFs activate pathways like TGF-β and PDGF, driving tumor growth and chemotherapy resistance. (F) The TME’s signaling networks involve interactions among various cell types. Tumor cells and CAFs activate pathways like TGF-β and PDGF, driving tumor growth and chemotherapy resistance.