Abstract
Soft tissue manipulation (STM) is widely used by physical therapists, massage therapists, athletic trainers, and osteopathic physicians to manage musculoskeletal pain, yet its biological mechanisms remain poorly understood. Preclinical studies indicate that STM can alter immune cell behavior in animal models, increasing anti-inflammatory cytokines (IL-4, IL-10) and reducing chemokines such as RANTES/CCL5. Single-cell transcriptomic analyses suggest mechanical treatment may reprogram stromal cells and shift immune cell recruitment in aged or inflamed tissues. However, many of these mechanistic findings have yet to be confirmed in human studies. Early clinical trials show massage therapy can modify circulating leukocytes and reduce cytokine responses, but direct tissue-level evidence in human subjects remains limited. This narrative review summarizes existing insights and emphasizes the need for future clinical investigations targeting populations with chronic inflammation, repetitive-use injuries, post-surgical fibrosis, or age-related muscle decline. We advocate for studies incorporating tissue or fluid sampling, cytokine profiling, and molecular assays such as flow cytometry or transcriptomics to characterize STM's immunological effects in people. Rather than simply easing symptoms, STM may act as a precision mechanical stimulus that recalibrates immune tone and promotes tissue repair. Bridging basic science with clinical research will be essential to establish STM as a biologically informed, mechanobiology-based therapeutic strategy.