Exploitation of lipid metabolism in improving cancer immune checkpoint therapy response

Immune-checkpoint inhibitor therapy (ICI), aimed at enhancing CD8+ T-cell activity against solid tumours, is revolutionising cancer management, providing unprecedented and sustained responses in several cancer types, including melanoma, clear cell renal cell carcinoma and lung cancer. Unfortunately, only a subset of patients benefits from ICI, emphasizing the need for strategies that sensitise tumours to ICI. Here, by analogy with other immune-related diseases and based on strong preliminary data, we propose that poly-unsaturated fatty acids (PUFA) and particularly their oxygenated metabolites, play a crucial role in immune responses and can be exploited to attract and activate CD8+ T-cell and to improve immune responses. Using cutting-edge technologies, including mass spectrometry imaging (MSI) of ICI-responsive versus non-responsive clinical tumors, we aim 1) to identify lipid profiles and PUFA metabolites that are associated with different ICI responses in cancer, 2) to validate the role of the identified lipid metabolites and related enzymes in immune cell infiltration and fate, and 3) to design strategies to exploit lipid metabolism in enhancing immune-cancer cell killing.