ORY1001 enhances anti-tumor immunity via CXCL10-mediated macrophage modulation in EBV-positive DLBCL.

Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment (TME), where tumor-associated macrophages (TAMs) often exhibit an M2-like phenotype that facilitates immune evasion. Here, we show that the LSD1 inhibitor ORY1001 reprograms the TME of EBV+ DLBCL through CXCL10-mediated modulation of macrophage polarization. Using a reductionist model in which EBV-negative DLBCL cell lines were transfected with LMP1, we demonstrate that ORY1001 induces robust expression of CXCL10, TNF-α and IL-6 in LMP1+ Riva cells, promoting M1 macrophage differentiation and reprogramming M2 macrophages toward a pro-inflammatory phenotype. This CXCL10-driven macrophage reprogramming was also observed in an additional LMP1+ DLBCL line (U2932) and in primary EBV+ DLBCL cells, in which ORY1001 selectively increased CXCL10 levels in tumor-cell supernatants, and conditioned media from these cultures—but not direct ORY1001 exposure—drove M1 polarization of THP-1 and primary CD14+ monocytes. These effects were dependent on CXCL10-CXCR3 signaling, as pharmacological inhibition of CXCR3 abrogated M1 polarization. In vivo, ORY1001 suppressed tumor growth in LMP1-expressing A20 lymphoma models, increased CXCL10 levels, and enhanced M1 macrophage infiltration. Furthermore, ORY1001 synergized with anti–PD-1 therapy to enhance T-cell activation, granzyme B expression, and tumor regression. These findings highlight LSD1 inhibition as a promising immunoepigenetic strategy to remodel the TME and improve the efficacy of immune checkpoint blockade in EBV-associated lymphomas.