Predictors of sensitivity to immune therapies in classic Hodgkin lymphoma.

Immune checkpoint blockade, particularly programmed cell death protein 1 inhibition, has redefined the management of classic Hodgkin lymphoma (cHL), achieving unprecedented efficacy in relapsed/refractory settings. Yet, durable benefit is not universal, because 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, previous treatment exposure, CD30 intensity, programmed death-ligand 1 (PD-L1)/PD-L2 copy number gains, and loss of major histocompatibility complex 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, whereas circulating biomarkers such as soluble PD-L1, circulating tumor DNA kinetics, and cytokine profiles provide noninvasive insights. Molecular and cellular pathways underlying resistance encompass genetic and epigenetic alterations, immune editing, and adaptive checkpoint upregulation. Emerging predictive frameworks, spanning multiomics and spatial profiling, radiomics, artificial intelligence, and microbiome-host cross talk, 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.