γ-Tocotrienol Sensitises Colorectal Cancer to PD-1 Blockade by Enhancing MHC-I-Associated Tumour Immune Visibility...

γ-Tocotrienol (γ-T3), a naturally occurring vitamin E isoform from plant-derived sources, has attracted attention as an antitumour agent. However, whether γ-T3 can enhance antitumour immunity and improve immune checkpoint blockade remains unclear. Here, using colorectal cancer (CRC) models, we found that γ-T3 suppressed tumour growth in immunocompetent MC38 and CT26 mouse models, whereas this effect was markedly weakened in immunodeficient hosts, indicating that its in vivo antitumour activity is closely associated with host immunity. Combination treatment with γ-T3 and programmed cell death protein 1 (PD-1) blockade further improved tumour control, accompanied by enhanced CD8⁺ T cell effector function, reduced regulatory T cell abundance, and tumour-associated macrophage remodelling towards an antitumour phenotype. Immune cell depletion experiments confirmed that CD8⁺ T cells are the principal effector cells mediating γ-T3-associated tumour suppression. Mechanistically, HSPA4 was identified as a candidate γ-T3-associated protein potentially linked to MHC-I-related immune-recognition features. γ-T3 promoted the expression of Psmb8 and Tap2 and increased MHC-I surface levels on tumour cells, accompanied by increased sensitivity of tumour cells to activated CD8⁺ T cell-mediated growth inhibition. These findings support γ-T3 as a naturally derived immune-sensitising agent for improving PD-1 blockade therapy in CRC.