Cancer cell invasion is one of the deadliest aspects of cancer, as it enables tumor cells to evade therapy and establish metastatic sites in distant organs. Metastasis disrupts tissue structure and organ function throughout the body, leading to poor patient survival. Because cell migration underlies invasion, understanding how tumor cells move is critical for identifying new therapeutic targets. The tumor microenvironment, composed of surrounding cells and the extracellular matrix (ECM), determine invasion strategies. Cells interact with the ECM by adhering, remodeling, or degrading matrix proteins, thereby altering stiffness, porosity, and alignment. These matrix properties in turn regulate how cells migrate, through a process known as mechanotransduction. The cytoskeleton, composed of actin, microtubules, intermediate filaments, and septins, governs cellular mechanics and integrates signals from ECM adhesions. Crosstalk between cytoskeletal networks fine-tunes invasion by coordinating deformability, contractility, and adhesion. In this thesis, we study how cell-matrix interactions and cytoskeletal crosstalk determine cancer cell invasion strategies using diverse in vitro models. Microfluidic chips allow us to probe migration in confined geometries, hydrogels mimic the ECM architecture, and 3D spheroids model multicellular invasion. We show that cancer cell mechanics strongly influence migration efficiency in confined environments. Moreover, we demonstrate that ECM porosity and cytoskeletal elements such as vimentin regulate the onset and rate of invasion. Our work further reveals that septins support breast cancer invasion by modulating cell shape and actin protrusions. Finally, we discuss how future studies can address the dual role of plectin-mediated cytoskeletal crosstalk in promoting and inhibiting invasion. Together, this thesis highlights the complex but central role of cell-matrix interactions and cytoskeletal crosstalk in shaping cancer cell invasion strategies.