Macrophage PAK2 controls the SIRPα immune checkpoint via cytoskeletal dynamics and endocytic trafficking

Professional phagocytes are essential for immunomodulation, antimicrobial control, and initiation and resolution of inflammation. These cells rely on dynamic cytoskeletal rearrangements to respond to their environment. This plasticity requires a network of positive and negative regulators to control biomechanics and signaling circuits. P21-activated kinases (PAKs) regulate the actomyosin cytoskeleton, cell proliferation, and gene expression, yet their contributions to phagocyte functions remain unresolved. Analyzing PAK1/2-deficient phagocytes and utilizing a PAK inhibitor we show that PAK2 governs physio-mechanical macrophage properties, leading to membrane expansion, hyperphagic behavior and disruption of endocytic transport when absent, while PAKs cooperate to restrain oxidative neutrophil responses. In PAK1/mPAK2 ablated mice cytoskeletal remodeling combined with low-grade chronic inflammation prompts the spontaneous development of a macrophage-driven hematologic malignancy. Macrophage PAK2 ablation or inhibition markedly enhances cancer cell uptake by exerting biophysical control over the CD47-SIRPα checkpoint, indicating that biomechanical modification of macrophages holds promise in cancer immunotherapy.