Using several murine and human CRC cell models, we demonstrated that LPCAT2-mediated accumulation of LDs contributes to CRC cell resistance to several chemotherapies (e.g., 5-FU, oxaliplatine, FOX) without impacting cell growth ability, evidencing the key role of these organelles in the protection of tumor cells against intrinsic and extrinsic cell death. Here, LPCAT2 is linked to colorectal carcinoma.