Progressive multiple sclerosis (PMS) represents a distinct clinical and biological entity characterized by compartmentalized neuroinflammation, chronic glial activation, and resistance to conventional immunotherapies. Unlike relapsing MS, PMS is sustained by resident CNS immune networks, where activated microglia and astrocytes orchestrate persistent cytokine signaling—particularly involving TNF-α, IL-1β, and IL-6—through self-amplifying feedback loops. In this narrative review, we explore how these cytokines interact with oxidative stress, iron accumulation, mitochondrial dysfunction, and impaired autophagy to drive neurodegeneration. Human-based evidence is integrated with insights from experimental models to clarify translational mechanisms. We also highlight fluid biomarkers (e.g., GFAP, NfL) and imaging modalities (e.g., TSPO-PET, QSM) that reflect glial activity and disease progression in vivo. Age, sex hormones, and immunosenescence are discussed as modulators of cytokine expression. Finally, we review emerging therapeutic strategies that target glial metabolism and cytokine networks rather than peripheral immune cells, offering a systems-based framework for future PMS interventions and personalized disease monitoring.