CAR T therapy is constrained by life-threatening cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), interrelated toxicities with poorly defined upstream triggers. While both toxicities involve aberrant myeloid activation, their shared initial drivers remain elusive. Through proteomic profiling of patient samples, we identified secreted tryptophanyl-tRNA synthetase (WRS) as a key signature of these adverse events. Cohort analyses reveal plasma WRS as a unifying predictive biomarker for both toxicities. Mechanistically, aggregated WRS, not the diffused form, is pathogenic under the low-sodium microenvironment. Aggregated WRS was detected in both the plasma and central nervous system under pathological conditions, and functionally validated as a potential driver of both toxicities. Therapeutically targeting the WRS circuit in humanized mouse models attenuates both systemic and neurological toxicities. Our bedside-to-bench investigative pipeline establishes WRS as a molecular nexus linking CRS and neurotoxicity, offering an integrated strategy to improve CAR T treatment safety.