Saturated fatty acid chain length shapes B cell lymphoma metabolism and progression

B-cell lymphomas reprogram cellular metabolism to sustain their rapid growth and proliferation. Despite their close proximity to adipose tissue and the paradoxical association between obesity and improved lymphoma outcomes, how fatty-acid availability and dietary fat composition influence B-cell lymphoma remains poorly understood. Importantly, saturated fatty acids of different chain lengths have distinct routes of cellular uptake and metabolic fates and may therefore exert divergent effects on tumour growth. Here, we investigated how medium-chain and long-chain saturated fatty acids, their dietary availability, and their transfer from adipocytes shape B-cell lymphoma metabolism and progression. We found that B-cell lymphoma cells were dependent on fatty-acid uptake, activation, and utilization for proliferation. Additionally, we identified adipocytes as microenvironmental players that transfer fatty acids and suppress cell growth. Interestingly, in most B-cell lymphomas, exogenous palmitate limits lymphoma cell proliferation, while MCFA caprylic acid showed only mild effects. Using a syngeneic B-cell lymphoma orthotopic model, we found that an MCFA-rich diet increased lymphoma burden and accelerated lymph-node progression, whereas LCFA-rich and obesogenic diets restricted lymphoma dissemination. Dietary fatty-acid composition also altered T-cell exhaustion and profoundly remodelled the circulating lipidome, with LCFA-rich and obesogenic diets producing highly concordant lipidomic signatures distinct from MCFA feeding. Across B-cell lymphoma cell lines, low ACSL1 expression was associated with increased palmitate sensitivity, which we computationally modelled as a targetable vulnerability in B-cell lymphoma treatment. Taken together, our results show that lipid metabolism is a metabolic vulnerability that can be targeted through dietary intervention.