Abstract In high-grade lymphatic malignancies, such as Burkitt’s lymphoma (BL), macrophage infiltration represents a characteristic morphological hallmark. Although macrophages can be directly cytotoxic against tumor cells, tumor associated macrophages (TAMs) regularly fail to kill them. The mechanism responsible for this loss of function remains unknown. Here, we firstly demonstrate that M1 (classically activated) macrophages selectively kill proliferating lymphoma cells by releasing the antimicrobial peptide cathelicidin in a vitamin D dependent fashion. Moreover, we show that cathelicidin leads to cell death by targeting the mitochondria. In contrast, M2 (alternatively activated) macrophages, and M2-like TAMs in BL exhibit an altered vitamin D metabolism that leads to reduced production of cathelicidin and consequently failure to lyse lymphoma cells. However, treating M2 macrophages with 1,25D or a vitamin D receptor agonist efficiently triggers cathelicidin-mediated tumoricidal activity against BL cells. Taken together, these observations indicate that a therapeutic activation of the vitamin D pathway could restore antitumor activity of TAMs, which are an important player in the tumor stroma. Disclosures: Mackensen: Eli Lilly: Consultancy.