The puzzle of why most colorectal cancers resist immunotherapy may have found a molecular answer in an unexpected place: dietary fat metabolism. This discovery could unlock new treatment strategies for the 85% of colorectal cancer patients whose tumors currently evade immune checkpoint blockade therapies.
Researchers identified that palmitic acid, a common saturated fatty acid from diet and metabolism, chemically modifies the immune checkpoint protein B7H3 through a process called palmitoylation. The enzyme ZDHHC24 adds palmitic acid to B7H3 at a specific amino acid position (cysteine 496), preventing the protein's normal degradation pathway. This modification blocks B7H3 from binding to SQSTM1, a protein that typically tags it for cellular cleanup through autophagy. The result: B7H3 accumulates to abnormally high levels, creating a powerful shield that suppresses CD8+ T cells from attacking the tumor.
This metabolic-immune connection represents a fundamentally different therapeutic angle than current checkpoint inhibitors. While existing drugs like anti-PD-1 therapies work in only 15% of colorectal cancers, targeting this palmitoylation pathway showed promise across broader tumor types in mouse models. The research team engineered a cell-penetrating peptide that disrupts the ZDHHC24-B7H3 interaction, successfully reactivating immune responses and enhancing the effectiveness of PD-1 blockade. The findings suggest that colorectal cancer's notorious immunotherapy resistance may stem partly from hijacked fat metabolism rather than just genetic immune evasion mechanisms. This opens potential for combination approaches targeting both metabolic and immune pathways simultaneously.