Despite advances in reducing treatment-related toxicities, predictive biomarkers for bleomycin-induced pulmonary toxicity (BPT) remain undefined. Affecting around 10% of classic Hodgkin lymphoma (CHL) and associated with a mortality rate of 10-20%, BPT poses a clinical challenge. This study aimed to characterize the pre-therapeutic nodal tumor microenvironment in CHL patients with and without BPT development. Gene expression profiling (GEP) was performed on diagnostic lymph node biopsies from CHL patients who developed BPT (T-CHL, n = 23) during treatment and those who did not (nT-CHL, n = 47). Differential protein expression of MIF, pSTAT3, LILRB3, and CD206 was further assessed with immunohistochemistry (IHC) in an evaluation cohort (n = 285). GEP revealed T-CHL samples enriched in genes associated with immune regulation and inflammation (STAT3, LILRB3, MIF), fibrosis and tissue remodeling (CD206), and immune signaling and regulation of apoptosis (JAK3) compared with nT-CHL. IHC confirmed higher pSTAT3 (p = 0.001) and CD206 (p = 0.029) expression in T-CHL and lower MIF and LILRB3 expression (both p < 0.001) compared with nT-CHL. These findings suggest that immune and fibrotic signatures in diagnostic biopsies may predict BPT risk. Early identification of high-risk patients could enable personalized treatment approaches that reduce toxicity while maintaining efficacy, positioning tumor microenvironment profiling as a promising strategy for optimizing CHL care.