Bone voyage: OPN's path from skeleton to systemic immunosuppression

Abstract

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment across multiple tumor types. However, some patients receive limited benefit, and the underlying mechanisms of resistance remain a formidable challenge, spurring intensive research efforts. A recent study published in Cancer Cell reveals that bone metastases actively suppress systemic anti-tumor immunity and contribute to ICB resistance. Analysis of clinical cohorts showed that patients with bone metastases exhibit reduced responsiveness to ICBs. Mechanistically, the study demonstrated that intraosseous tumors enhance osteopontin (OPN) production by osteoclasts. Circulating OPN was found to impair differentiation of progenitor exhausted T cells (Tpex), a subset correlated with ICB responsiveness, in distant tumor sites, thereby blunting anti-tumor immune response. Importantly, osteoclast-specific depletion of OPN or inhibition of osteoclastogenesis restored T cell function and enhanced ICB efficacy in preclinical cancer models, suggesting that targeting osteoclasts overcomes ICB resistance in patients with bone metastases. This study offers novel insights into the role of OPN, revealing its capacity to traverse from the skeletal microenvironment to distant sites, orchestrating widespread immunosuppression that extend well beyond the bone itself. As a pioneering investigation, it delineates the immunosuppression mechanism mediated by the osteoimmune axis and represents a significant advancement in the emerging field of osteoimmunology.