Mechanoimmunology in the solid tumor microenvironment

Abstract

The tumor microenvironment (TME) is a complex and dynamic ecosystem that adjoins the cancer cells within solid tumors and comprises distinct components such as extracellular matrix, stromal and immune cells, blood vessels, and an abundance of signaling molecules. In recent years, the mechanical properties of the TME have emerged as critical determinants of tumor progression and therapeutic response. Aberrant mechanical cues, including altered tissue architecture and stiffness, contribute to tumor progression, metastasis, and resistance to treatment. Moreover, burgeoning immunotherapies hold great promise for harnessing the immune system to target and eliminate solid malignancies; however, their success is hindered by the hostile mechanical landscape of the TME, which can impede immune cell infiltration, function, and persistence. Consequently, understanding TME mechanoimmunology — the interplay between mechanical forces and immune cell behavior — is essential for developing effective solid cancer therapies. Here, we review the role of TME mechanics in tumor immunology, focusing on recent therapeutic interventions aimed at modulating the mechanical properties of the TME to potentiate T cell immunotherapies, and innovative assays tailored to evaluate their clinical efficacy.

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

“…These alterations collectively create a distinct mechanical microenvironment that impacts the behavior of cancer cells and stromal cells, especially immune cells and fibroblasts, by modulating their migration and activation within the TME [11,12]. For example, a stiffened ECM activates mechanotransduction pathways (e.g., the YAP/TAZ, Rho/ROCK, and cell nuclear deformation pathways), promoting cancer cell survival, proliferation, migration, and drug response [2,13,14]. Additionally, the reorganization of ECM fibrils into aligned structures and microarchitecture facilitate fibroblast-to-myofibroblast differentiation via cell contractility [15,16], reduces the T-cell immune response via YAP signaling [17], and enhances cancer cell invasion, potentially aiding metastasis [18][19][20].…”

“…M1 macrophages are generally associated with tumorsuppressing functions, including promoting inflammation, producing reactive oxygen species, and facilitating antigen presentation to T cells. These activities help attack and destroy cancer cells in the early stages of tumor development [13,24]. In contrast, M2 macrophages are associated with tissue repair and immunosuppression, facilitating tumor growth and metastasis.…”