Colorectal cancer responds poorly to immune checkpoint blockade in most patients with microsatellite-stable (MSS) tumors, highlighting the need for alternative targets. B7H3 (CD276) is an immune checkpoint protein that is frequently overexpressed in tumors, but how it is maintained at high protein levels is unclear. Here we show that palmitic acid (PA) promotes B7H3 palmitoylation by the palmitoyltransferase ZDHHC24 at cysteine 496. This modification prevents B7H3 from binding to sequestosome 1 (SQSTM1, also called p62), limiting autophagic degradation and stabilizing B7H3, which suppresses CD8+ T cell antitumor activity. Disrupting this pathway by mutating cysteine 496, or by deleting Zdhhc24 in a colitis-associated colorectal cancer (CAC) mouse model, enhances CD8+ T cell responses. We also develop a cell-penetrant peptide that blocks the ZDHHC24-B7H3 interaction, boosts antitumor immunity, and synergizes with blockade of programmed cell death protein 1 (PD-1). These findings identify B7H3 palmitoylation as a targetable metabolic-immune node for colorectal cancer immunotherapy.
© 2026. The Author(s).