Figure 3. The physical landscape of the peritumor directly and indirectly affects the activity of immune cells to activate or suppress immunity.

Alterations to the four physical hallmarks of cancer – solid stress, fluid flow, stiffness, and microarchitecture – can have direct effects on immune cell activity (color-coded lines from attribute to specific cell type). These effects can be activating (sharp arrow) or inhibitory (blunt arrow) and are highly interconnected. Attributes may indirectly modulate immune cell behavior through intermediate signaling pathways. Prominent among these immunomodulatory molecules are: immune-inhibitory programmed death-ligand 1 (PD-L1), anti-inflammatory cytokine transforming growth factor β (TGF-β), matrix crosslinking enzyme lysyl oxidase (LOX), matrix remodeling matrix metalloproteinase-9 (MMP-9), and macrophage-specific transcription factors STAT3/6. The highly interrelated nature of the peritumor environment means that immune cells can be indirectly impacted by pathways which are up- or down-regulated by the physical microenvironment, which may then further activate (black sharp arrow) or inhibit (black blunt arrow) immune cells or immunomodulatory pathways. We illustrate the connections between the abundant elements that interact with mechano-immunity in the peritumor, and list the major components in Table 1 in the main text.