Mechanical Immune Checkpoints in Tumors: Mechanosensing, Immunosuppressive Networks, and Therapeutic Modulation

Solid tumors undergo significant biomechanical remodeling, which includes ECM stiffening, collagen crosslinking and alignment, increased interstitial fluid pressure, solid stress, vascular compression, and altered viscoelastic properties. These biomechanical abnormalities function not merely as passive structural features but actively influence tumor progression and immune evasion. Emerging evidence introduces the concept of mechanical immune checkpoints, defined as mechanosensory immunoregulatory circuits that link specific biomechanical signals to impaired antitumor immunity through identifiable mechanosensory or mechanotransduction pathways This review first summarizes the mechanisms through which aberrant tumor mechanics contribute to T-cell exclusion, T-cell exhaustion, suppressive myeloid differentiation, and stromal remodeling. Subsequently, it discusses therapeutic strategies, including ECM remodeling, inhibition of mechanotransduction, modulation of mechanosensors and tumor cell stiffness, as well as rational combinations with traditional immune checkpoint blockade. Lastly, the translational maturity of current strategies is critically assessed, highlighting priorities for biomarker-guided combination therapy. By conceptualizing force-sensitive immunosuppressive circuits within a clinically relevant framework, mechanical immune checkpoints may facilitate biomarker-guided patient stratification and rational combination approaches to enhance immunotherapy efficacy in mechanically resistant solid tumors.