The neurodegenerative condition ‘chronic traumatic encephalopathy’ (CTE) is an environmental tauopathy that is found almost exclusively in individuals with a history of repeated exposure to head trauma. CTE has risen to prominence in the public consciousness, principally because of its link to professional (and lucrative) contact sports. At present, CTE is very poorly understood, and only able to be diagnosed by post-mortem examination of the brain. There is a pressing need to understand the pathophysiology of the disease, and identify biomarkers for diagnosis during life. CTE lesions can only be detected by visualising hyperphosphorylated tau deposition, and lesions are typically randomly distributed through the cortex, rendering bulk approaches to molecular analysis difficult and often confounded. We have addressed this by performing spatially resolved transcriptomics within and around known CTE lesions in human dorsolateral prefrontal cortex using the10x Visium platform. Within densely tau-positive CTE lesions, we observed altered expression of hundreds of genes across multiple lesions; overexpression of four genes (GFAP, APNLR, AQP1, TNC) was universal. Together the alterations signified a complex molecular response to brain trauma, including heightened astrocytic activity, neuroinflammation, altered blood-brain barrier function, and extracellular matrix remodelling. When unaffected brain areas were compared to normal cortex and that from Alzheimer’s disease there were intriguing changes in the first cortical layer, where increased expression of RELN and NDNF defined those brains where CTE was present distally. This may indicate a compensatory response to neuronal loss, offering valuable insights into the brain's adaptive mechanisms in CTE. Together these gene expression signatures provide the first glimpse into the intricate molecular dynamics underlying CTE. They also potentially serve as diagnostic markers for definitive in life diagnosis and/or targets for therapeutics.