Immunity and inflammation in classic Hodgkin lymphoma: Bridging diagnosis, prognosis and precision medicine.

Abstract

Classic Hodgkin lymphoma (cHL) is a unique B-cell malignancy characterized by a small number of malignant Hodgkin and Reed-Sternberg (HRS) cells embedded within an extensive and highly organized inflammatory microenvironment. Recent studies have highlighted that the biological behavior of cHL is largely determined by dynamic interactions between HRS cells and surrounding immune populations, including CD4+ T cells, regulatory T cells, macrophages, eosinophils, mast cells, natural killer cells, and stromal elements. HRS cells actively reshape the tumor microenvironment through the secretion of chemokines and cytokines, including CCL17, CCL22, IL-6, IL-10, and TGF-β, promoting immune cell recruitment, chronic inflammation, and immune tolerance. Concurrently, genetic alterations affecting the PD-1/PD-L1 axis, antigen-presentation pathways, and key signaling cascades such as NF-κB and JAK/STAT facilitate immune escape and tumor persistence. We distinguish diagnostic, prognostic, predictive, and response-monitoring applications and grade biomarkers as established (immunophenotyping, EBER, clinical scores, interim PET), clinically promising (serum TARC, circulating tumor DNA), or investigational (PD-L1-based prediction, spatial and single-cell profiling, artificial intelligence). A deeper understanding of the interplay between immunity and inflammation in cHL may refine disease classification and guide the development of novel immunomodulatory strategies aimed at improving long-term outcomes and overcoming resistance to current therapies.