<p>Surface mechanical regulation has emerged as a transformative paradigm for programming macrophage behavior, positioning mechano-engineered interfaces as potent tools for next-generation immunotherapies and regenerative medicine. Mechanical cues embedded within material surfaces, including stiffness, viscoelasticity, roughness, and micro-/nano-patterning, function as active instructive signals that train macrophages by modulating cytoskeletal tension, nuclear mechanics, and chromatin accessibility, thereby reorienting polarization states and immune functions. Recent discoveries further reveal that surface mechanics can imprint durable phenotypic and epigenetic changes, enabling precise control over pro-regenerative, anti-inflammatory, or antitumor macrophage programs. This review synthesizes these emerging insights and outlines how mechano-bioengineered platforms reshape the immune microenvironment through macrophage-centered modulation, while also examining key translational challenges, including in vivo mechanical stability, long-term biocompatibility, and spatiotemporal precision of immune activation. Advances in artificial intelligence and computational design are additionally accelerating the development of personalized mechanoregulatory surfaces and optimizing macrophage-targeted therapeutic strategies. Collectively, these developments establish surface mechanical regulation as a novel and powerful strategy for macrophage training, opening new avenues for clinical translation in disease treatment and tissue regeneration.</p> Graphical Abstract <p></p>