Mechanical and chemical macrophage activation differ by arm, not by amplitude

Mechanical perturbation of macrophages shifts the ISGF3-dependent interferon-stimulated gene module by only −0.9% versus the chemical M1 anchor, effectively zero within ±10%.

• Why it matters: Prior claims that stiffness mechanically drives an M1-like program rely on inconsistent NF-κB/AP-1 marker scaling and disagree on stiffness direction, leaving the true relationship unclear.
• What they did: Ten independent substrate stiffness/force studies were rescored against LPS + IFN-γ chemical anchors using an identical pipeline, with shifts also tested across multiple ISG definitions and ten additional mechanical modalities.
• The result: Mechanics rewires thousands of genes but leaves the ISGF3 module within a size-matched random distribution; when rescored to an NF-κB effector module, the effector arm rises while the interferon arm falls.

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