Haoming Ning, Kejia Yang, Yu Zhang, Junjun Liu, Xueqin Zhu, Chunxia Chen, Qingyu Dong, Wenzhi Shang, Xiaoshuang Chen, Xin Yang, Rui Liang, Yang Li, Yuzhen Qian, Yixuan Sun, Xiuman Zhou, Yi Liu, Nan Li, Qingyang Zhao, Yanfeng Gao
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.