Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive form of non-Hodgkin lymphoma. While standard therapies are effective for many patients, outcomes remain poor after first relapse and for high-risk subtypes such as “double-hit” DLBCL, which is driven by alterations in the oncogene MYC and associated with rapid disease progression and limited treatment success. 

This project focuses on the lymphoma microenvironment, a key factor influencing cancer development and therapy response. In particular, it investigates tumour-associated macrophages (TAMs), immune cells that can either attack tumour cells or support their growth. In DLBCL, TAMs are predominantly reprogrammed into a lymphoma-supportive state, contributing to poor prognosis. Emerging evidence suggests that lymphoma cells actively shape macrophage behaviour through metabolic interactions. The oncogene MYC is also a powerful regulator of cellular metabolism and may play a critical role in this process. However, the mechanisms by which MYC alters TAM function remain largely unknown. The aim of this project is to uncover how MYC-driven metabolic changes in lymphoma cells influence TAM behaviour and to identify strategies to reverse lymphoma-supportive macrophage functions. A particular focus lies on the pentose phosphate pathway, a metabolic pathway regulated by MYC, that has already been shown to control macrophages’ anti-lymphoma activity. Building on strong preliminary data demonstrating that metabolic intervention can reprogram macrophages towards an anti-tumour state, this project combines advanced imaging technologies with molecular and functional analyses to map metabolic interactions within the lymphoma microenvironment. By identifying key mechanisms of lymphoma–immune interaction, this research aims to develop new therapeutic strategies that do not eliminate macrophages but instead reprogram them to support anti-lymphoma immunity. Ultimately, this approach has the potential to improve treatment outcomes for patients with high-risk DLBCL and contribute to the development of more effective, targeted therapies.

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