Predictors of sensitivity to immune therapies in classic Hodgkin lymphoma

Immune checkpoint blockade, particularly PD-1 inhibition, has redefined the management of classic Hodgkin lymphoma (cHL), achieving unprecedented efficacy in relapsed/refractory settings. Yet, durable benefit is not universal, as mechanisms of primary and acquired resistance remain incompletely understood. This review integrates current knowledge on predictors of sensitivity to immune therapies in cHL across clinical, biological, and technological dimensions. Established predictors, including disease burden, prior treatment exposure, CD30 intensity, PD-L1/PD-L2 copy-number gains, and loss of MHC expression, offer valuable but incomplete prognostic information. Tumor microenvironmental features such as macrophage polarization, T-cell exhaustion, and immune spatial organization further refine response prediction, while circulating biomarkers like soluble PD-L1, ctDNA kinetics, and cytokine profiles provide non-invasive insights. Molecular and cellular pathways underlying resistance encompass genetic and epigenetic alterations, immune editing, and adaptive checkpoint upregulation. Emerging predictive frameworks, spanning multi-omics and spatial profiling, radiomics, artificial intelligence, and microbiome-host crosstalk, promise to enhance precision in patient stratification. Finally, the review outlines key challenges and research priorities for translating these multidimensional biomarkers into clinical trials and practice. A unified predictive framework integrating clinical, molecular, and computational indicators may ultimately enable personalized immunotherapy and overcome resistance in cHL.