<p>Aberrant mechanical signaling is a hallmark of solid tumors. Given that the brain is one of the softest tissues in the body, brain tumors develop within a unique mechanical microenvironment, where mechanical cues extensively regulate malignant behaviors and brain-tumor associated neuroinflammation. Growing evidence indicates that mechanical signals promote brain tumor progression by symbiotically regulating various immune cells and canonical neuroimmune pathways. Thus, targeting mechanical cues has emerged as a promising strategy in overcoming immunotherapy resistance. This review outlines the distinct characteristics of the mechanical microenvironment in brain tumors and the regulatory roles of mechanical forces in tumor progression, highlighting the key functions of mechanical force-mediated immune microenvironment remodeling in brain tumor immunosuppression and treatment resistance. Furthermore, we summarize mechano-targeting methods in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of mechanical signaling in the brain tumor microenvironment.</p>