For decades, cancer biology research has primarily focused on intrinsic tumor mechanisms driven by genetic lesions. It is now clear that tumor cell behavior is shaped by additional layers of regulation, including epigenetic modifications and metabolic reprogramming, which confer high plasticity and render cancer cells highly responsive to cues from their surrounding microenvironment. Continuous cross-talk between tumor cells and the diverse components of the tumor microenvironment dictates tumorigenesis and is often skewed toward pro-tumoral signals, thereby fueling cancer progression. In B-cell lymphomas, a heterogeneous group of malignancies arising from mature B cells, immune-tumor interactions are particularly important, especially in early disease and indolent subtypes. The increasingly precise understanding of these interactions has recently driven the development of immune-based therapies, which have achieved transformative results in both lymphomas and solid tumors. Nevertheless, tumors continuously adapt and evade immune control, and relapsed or refractory cancers remain largely incurable despite recent advances. Overcoming these limitations requires novel therapeutic strategies and preclinical models that reproduce the complexity of human disease.
In this thesis, I describe a strategy to enhance anti-cancer immunity by targeting long-chain fatty acid (LCFA) elongation. By combining high-throughput drug screening with proteomics, lipidomics, and genetic engineering, we identified Phago Booster 1 (PB1), a small-molecule inhibitor of HSD17B12, a key enzyme in LCFA elongation. Targeting HSD17B12 selectively altered membrane organization in cancer cells, leading to the redistribution of surface receptors, including immune checkpoints and lipid transporters. In contrast, HSD17B12 inhibition enhanced the cytotoxic capacity of immune cells by increasing their glycolytic activity, thereby promoting activation. This divergent effect proved therapeutically relevant in vivo, leading to slower tumor growth and improved survival without notable toxicity. In parallel, I contributed to the development of a patient-derived lymphoma tissue explant platform designed to preserve native tumor architecture, stromal components, and immune cell diversity. We demonstrated that this system, termed lymphomoids, can support personalized medicine approaches by enabling the ex vivo assessment of patient-specific therapeutic responses. In a pilot cohort of 8 patients, drug sensitivity in lymphomoids successfully matched clinical outcomes in 89% of cases, highlighting its potential as a predictive tool for guiding treatment selection.
Together, these approaches illustrate how combining innovative therapeutic discovery with physiologically relevant disease models can uncover actionable strategies to overcome immune resistance and advance personalized cancer treatment.
