Interactions between the tumor microenvironment and HRS cells in EBV-uninfected and EBV-infected cHL. The presence of enhanced immunosuppressive features, such as higher numbers of M2 macrophages and elevated expression levels of PD-L1, in EBV-related cHL should make EBV-related cHL more susceptible to checkpoint blockade. (A) The inflammatory/immune cell infiltrate of the tumor microenvironment and the molecules that support the growth and survival of HRS cells. (B) The contribution of LMP1, LMP2a, DDR1, PD-L1, and CD40 to the survival of HRS cells. Constitutive activation of NF-κB and JAK/STAT signaling pathway is the molecular hallmark of HRS cells. The expression of EBV-LMP1 is thought to contribute to activation of the NF-κB and JAK/STAT pathway.