Huntington’s disease (HD) is characterized by progressive striatal atrophy and complex proteomic changes in the central nervous system. Using the ultrasensitive Next-Gen Ultra-Sensitive Immunoassay (NULISA) proteomic platform, we analyzed cerebrospinal fluid (CSF) from 88 persons with HD to dissect the biological correlates of gray matter loss. Our findings reveal a distinct “Two-Track” model of pathology. The first track, marked by the axonal damage protein neurofilament light chain (NEFL), showed a strong inverse correlation with putamen volume (Pearson r = −0.53, p < 0.001), reinforcing its utility as a proxy for structural neurodegeneration. The second track was defined by a positive association between the immune regulator TNFRSF8 (CD30) and putamen volume (Pearson r = 0.36, p < 0.001), reflecting a decline in active immune-regulatory signaling as striatal atrophy advances. Given its established role in immune modulation, TNFRSF8 was pre-specified for follow-up to further interrogate this neuro-immune axis. Crucially, TNFRSF8 maintained an independent association with striatal volume (Beta = 0.24, p = 0.008) even after controlling for NEFL, genetic burden (CAG-Age Product score), and sex. Supplementary analyses confirmed that this structural–immune axis is localized specifically to the striatum—showing no association with generic structural control regions—and is driven by CAG repeat length rather than chronological aging. Furthermore, bidirectional mediation analysis supported an atrophy-driven model, where striatal volume statistically mediates the relationship between genetic burden and downstream immune dysregulation (p = 0.010). These results demonstrate that maladaptive immune signaling is a distinct pathological correlate in HD, separable from general cytoskeletal damage. This dual-axis framework warrants evaluation in larger longitudinal and interventional studies to guide future biomarker-driven patient stratification and target engagement.