Palmitic Acid-Triggerd B7H3 Palmitoylation Promotes Immune Escape

B7H3 (CD276), a key immune checkpoint molecule that is overexpressed in tumors, plays a central role in cancer progression, making it a highly promising and specific therapeutic target. Here, we discovered that the cellular metabolite palmitic acid contributes to the development of an immunosuppressive microenvironment in colorectal cancer by triggering the palmitoylation of B7H3. Mechanistically, the palmitoyltransferase ZDHHC24 catalyzes the palmitoylation of B7H3 at Cys496, preventing its binding to the autophagy adaptor protein SQSTM1/p62 and inhibiting autophagic degradation. Using spectral flow techniques, we demonstrated that the mutation of this palmitoylation site restored CD8+ T cell antitumor activity. Additionally, CD8+ T cells also showed enhanced antitumor activity in a Zdhhc24-deficient colitis-associated colorectal (CAC) carcinogenesis mouse model. Furthermore, we developed a small-molecule peptide that enhances CD8+ T cell function by blocking the interaction between ZDHHC24 and B7H3, which works synergistically with anti-PD-1 therapy. In conclusion, our study revealed that B7H3 C496 palmitoylation is a critical immunosuppressive factor in colorectal cancer and represents a potential target for malignant immunotherapy.