Tumor microenvironment and its implications for atomic force microscopy-based nanomechanics of cancer cells: a...

Forces are crucial for regulating physiological and pathological processes, and in particular, the mechanical phenotype of cancer cells has been appreciated as a promising biomarker that complements traditional biological features. Over the past few decades, atomic force microscopy (AFM)-based force spectroscopy has been widely used as an important method to characterize the nanomechanical properties of cancer cells, remarkably enhancing our understanding of tumorigenesis and metastasis from the biophysical perspective and making significant contributions to the field of cancer mechanobiology. Concurrently, it is increasingly apparent that tumor microenvironment is not a passive bystander but plays a pivotal role in shaping cancer cell functions and promoting tumor development. Nevertheless, the effect of the tumor microenvironment on cancer cell mechanics has long been omitted in experiments utilizing AFM to perform force measurements on cancer cells. The tumor microenvironment differs extensively from the healthy tissue in composition and structure, including altered extracellular matrix (ECM), aberrant blood vessels/lymphatic vessels, and the existence of diverse recruited cells (such as stromal cells and immune cells), which endows the tumor microenvironment with a variety of unique characteristics (e.g., solid stress, interstitial fluid pressure, hypoxia, acidity). Therefore, conducting AFM measurements on cancer cells under conditions resembling the tumor microenvironment is beneficial for exploring the faithful mechanical phenotype of cancer cells. There are emerging studies incorporating tumor microenvironmental cues into AFM detection of cancer cells, yielding additional insights into the mechanical behavior of cancer cells for a comprehensive understanding of tumor pathogenesis. This Perspective highlights the importance of considering tumor microenvironment in AFM-based nanomechanical analysis of cancer cells and discusses the future directions for advancing physical oncology.