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Although current anti-inflammatory therapies can alleviate symptoms, their capacity to arrest structural deterioration remains limited, underscoring the constraints of approaches that target inflammatory cytokines in isolation. This therapeutic intractability is rooted in the distinctive spinal microenvironment: high mechanical loading at the enthesis and the hypoxic niche of the intervertebral disc (IVD), through mechano-inflammatory coupling and maladaptive metabolic adaptation, actively drive pathological reprogramming of immune cells and create a barrier to the restoration of homeostasis. In this Review, we dissect the multidimensional crosstalk among biomechanics, metabolism and immunity, and delineate the central roles of Human leukocyte antigen B27 (HLA-B27) associated stress, metabolic reprogramming, and osteo-immune crosstalk in sustaining chronic inflammation. On this basis, we propose a paradigm shift from suppressing downstream mediators to modulating upstream microenvironments. We suggest that targeting metabolic checkpoints, interrupting mechanotransduction, and applying epigenetic interventions may promote inflammatory resolution and reset matrix homeostasis, thereby offering new strategies to restore spinal immune equilibrium and prevent structural failure.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1806060","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:30:10Z","timestamp":1781843410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Restoring immune homeostasis in the spinal microenvironment: targeting mechano-inflammation and immunometabolic reprogramming"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhichao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Chengdu Integrated TCM&Western Medicine Hospital","place":["Chengdu, 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