Myeloid immune reprogramming in bone metastatic cancer: Mechanistic crosstalk, therapeutic targets and unresolved clinical challenges.

Bone metastasis is a major clinical challenge in advanced solid tumors, driving skeletal-related events, chronic pain, and therapeutic resistance. Increasing evidence suggests that the bone metastatic niche is predominantly shaped by reprogrammed myeloid cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), neutrophils, and tolerogenic dendritic cells. These cells interact with osteoclasts and stromal components through RANKL, TGF-β, CSF-1/CSF-1R, CCL2/CCR2, and Siglec sialoglycan pathways to promote osteolysis, immune suppression, and metastatic expansion. This review critically synthesizes the mechanistic underpinnings of myeloid-driven immune remodeling in bone metastasis and evaluates current therapeutic strategies targeting this ecosystem. We highlight the limited effectiveness of immune checkpoint inhibitors in bone-dominant diseases and analyze emerging combination approaches that integrate PD-1/PD-L1 blockade with bone-modifying agents, TGF-β inhibition, and experimental therapies that modulate myeloid recruitment, polarization, or effector functions. We also assess challenges in clinical translation, including tumor-type heterogeneity, insufficient biomarkers, and incomplete understanding of spatial immune architecture within bone lesions. Advancing myeloid-targeted interventions may enable more durable control of metastasis and improve outcomes for patients with skeletal involvement.