Progressive multiple sclerosis (MS) is driven by persistent neuronal injury, causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent and unmet clinical need, yet is constrained by an incomplete understanding of its complex pathogenesis. Here, we performed spatial transcriptomics and proteomics of progressive MS brain tissue to delineate this complexity and to translate our findings into therapeutic targets aimed at rescuing dying neurons. We discovered micro-areas of structurally intact cortex, which exhibited reduced neuronal pro-survival signals within an imbalanced pro- and anti-inflammatory milieu, unmasking new therapeutic possibilities to prevent further decline. Spatially resolved ligand–receptor interactome analysis identified targetable intercellular interactions including G-protein coupled receptor GRP37L1 and growth factor receptors, such as FGFR3, which are central to the survival of CNS cells, in prticular neurons. These findings place progressive MS in a new light and provide promising opportunities to overcome neurodegeneration.