Spatial transcriptomics reveals molecular mechanisms underlying neuroinflammatory and neurodegenerative sequelae of immune checkpoint inhibition [MERFISH]

MERFISH revealed upregulation of microglial, astrocytic, oligodendrocytic and T cell markers post-ICI treatment, implicating pathways involved in neuroinflammation, synaptic function, and cellular signaling. Immunofluorescence analysis corroborated these findings in postmortem brains from patients treated with ICIs and demonstrated elevated microglial activation and astrogliosis, along with reduced expression of myelin sheath stability markers.

Mechanistically, conditional T cell depletion in a transgenic mouse model revealed that ICI-mediated microglial activation is contingent on the presence of T cells, thus establishing a causal T cell-microglia crosstalk axis driving neuroinflammation. Collectively, this work provides a high-resolution framework for understanding ICI treatment-associated neurotoxicity and establishing a significant link with neuroinflammation-associated cognitive decline, while also revealing potential molecular targets for therapeutic intervention.