HRS cells orchestrate the infiltration and activation of multiple cell types into the lymphoma microenvironment by secretion of cytokines and chemokines. Eosinophils and mast cells may stimulate HRS cells through CD30-CD30L interactions, whereas neutrophils may stimulate HRS cells through APRIL-BCMA interactions and the secretion of nerve growth factor (NGF), which binds to the receptor tyrosine kinase TRKA on HRS cells. The cellular interactions between CD4⁺ Th cells likely involve adhesion molecules (CD54-CD18/11a) and key molecules of B cell–T cell interaction, i.e., CD40-CD40L and CD80-CD28. Cytotoxic T cells and NK cells are inhibited through Tregs by secretion of IL-10, and perhaps additional mechanisms, and directly by the HRS cells though secretion of immunosuppressive mediators (IL-10, TGF-β). Cytotoxic T cells are furthermore inhibited by galectin1, secreted by HRS cells, and expression of PD-1L by HRS cells. CD95 ligand–expressing HRS cells may induce apoptosis of CD95⁺ cytotoxic T cells. Macrophage infiltration is of prognostic relevance, but the interactions between HRS cells and macrophages are only partly understood. Adapted with permission from Nature Reviews Cancer (2).