Discovery of a Potent APOBEC3B Inhibitor to Augment Antitumor Immunity and Reduce Inflammatory Toxicity.

APOBEC3B (A3B), a key driver of cancer mutagenesis, has emerged as a promising therapeutic target to be ablated to enhance antitumor immunity while reducing intestinal inflammation. Starting from SMC247 (3, 5-diiodotyrosine), a kelp-derived natural product, we identified the optimized analogue SMC247-9 as a potent A3B inhibitor, with an IC50 of 50 pM and KD value of 300 pM. SMC247-9 reduced cellular A3B abundance and promoted IL-15 expression in tumor cells, thereby relieving tumor cell-mediated suppression of CD8+ T cells in an IL-15-dependent manner. In immunocompetent mice, SMC247-9 suppressed tumor growth in the immune checkpoint blockade (ICB)-responsive MC38 model and synergized with anti-PD-L1 in the ICB-resistant TC-1 model. SMC247-9 also attenuated macrophage chemotaxis and ameliorated anti-PD-1-exacerbated DSS-induced colitis-like intestinal inflammation. These findings support A3B-targeted pharmacologic intervention as a strategy to enhance antitumor efficacy while reducing inflammatory toxicity in cancer immunotherapy.