Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis

Abstract Neuroinflammation is no longer a secondary feature of amyotrophic lateral sclerosis (ALS), but rather a disease-modifying process that actively shapes the motor neuron vulnerability from the earliest stages of pathology. Central and peripheral immune cells, including microglia, astrocytes, and infiltrating T lymphocytes, adopt context-dependent states that can be neuroprotective or neurotoxic depending on disease stage and genetic background. These states are driven by discrete molecular programs, such as cGAS-STING-mediated innate immune sensing, NLRP3 inflammasome activation, and RIPK1-dependent necroptotic signaling, which represent tractable therapeutic targets. The repeated failure of broad-spectrum immunosuppressive trials reflects a fundamental mismatch between the non-selective interventions and the mechanistically distinct immune states of diseases. Converging transcriptomic, genetic, and immunophenotypic evidence supports the existence of putative neuroimmune endotypes in ALS, though this framework remains a working hypothesis pending prospective validation in biomarker-stratified cohorts. Advances in the following three domains are needed for realizing precision immunotherapy: standardized biomarker panels (including cerebrospinal fluid chitinases and TSPO-PET) to stratify patients by inflammatory subtype; pharmacodynamic readouts to confirm target engagement before interpreting clinical outcomes; and adaptive platform trial designs capable of evaluating mechanism-matching interventions in defined subgroups. This review integrates ALS-associated neuroinflammation with emerging precision medicine strategies, arguing that the central translational question is no longer whether or not to target neuroinflammation, but how, when, and in whom neuroinflammation should be targeted.