ESMO Immuno-Oncology Congress 2024

Abstract 228P

Background

Recent research has emphasized the pivotal role of tumor-associated macrophages (TAMs) in shaping the efficacy of anti-tumor therapies. Metabolic reprogramming is a key driver of TAM polarization, influencing their pro-tumorigenic or anti-tumorigenic phenotypes. However, the precise mechanisms by which tumor cells manipulate TAM metabolism remain elusive. We have currently discovered that agonistic anti-CD40 antibodies promote anti-tumorigenic TAM activation by enhancing mitochondrial activity and modulating fatty acid oxidation (FAO). We further investigated the interplay between mitochondrial fitness and FAO in regulating TAM immunosuppressive functions.

Methods

We conducted a series of in vitro and in vivo experiments using mouse melanoma tumor models and bone marrow-derived macrophages (BMDMs) for this study.

Results

Our findings demonstrate that lipid-accumulated TAMs exhibit impaired mitochondrial activity, exacerbating their pro-tumorigenic properties. Tumor-derived lipids influence mitochondrial dynamics in TAMs, leading to increased FAO, mitochondrial reactive oxygen species (mtROS) production, and mitophagy. These metabolic alterations collectively contribute to the pro-tumorigenic phenotype of TAMs. Moreover, our research suggests that targeting mitochondrial dynamics-associated pathways may represent a promising therapeutic strategy to reverse TAM immunosuppression and enhance anti-tumor immunity.

Conclusions

This study provides valuable insights into the intricate relationship between lipid metabolism, mitochondrial dynamics, and TAM polarization within the tumor microenvironment (TME). By elucidating how lipid metabolism interacts with mitochondrial dynamics to modulate TAM phenotypes, we aim to develop innovative therapeutic approaches targeting these pathways to improve anti-tumor responses.