Cui Luying, Liu Ruiqi, Han Shuling, Zhang Chunhui, Wang Bojun, Ruan Yuli, Yu Xuefan, Li Yien, Yao Yuanfei, Guan Xin, Liao Yuanyu, Su Dan, Ma Yue, Li Shuijie, Liu Chao, Zhang Yanqiao
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China.
Cancer Res. 2025 Mar 3;85(5):925-941. doi: 10.1158/0008-5472.CAN-24-1611.
AT-rich interactive domain-containing protein 1A (ARID1A), a core constituent of the switch/sucrose nonfermentable (SWI/SNF) complex, is mutated in approximately 10% of colorectal cancers. Whereas ARID1A deficiency corresponds to heightened immune activity in colorectal cancer, immune checkpoint inhibitors (ICI) have shown limited efficacy in these tumors. The discovery of targetable vulnerabilities associated with ARID1A deficiency in colorectal cancer could expand treatment options for patients. In this study, we demonstrated that arachidonic acid (AA) metabolism inhibitors synergize with ICIs in ARID1A-deficient colorectal cancer by enhancing the activity of CD8+ T cells and inhibiting vasculogenic mimicry. Epigenetic analysis using ATAC-seq and ChIP-qPCR revealed that the lack of ARID1A results in reduced levels of PTGS1 and PTGS2, the key enzymes that control the AA pathway. Low PTGS1 and PTGS2 expression generated a reliance on the remaining functionality of the AA pathway in ARID1A-deficient cells. The AA pathway inhibitor aspirin selectively inhibited the growth of ARID1A-deficient colorectal cancer, and aspirin sensitized tumors lacking ARID1A to immunotherapy. Together, these findings suggest that blocking AA metabolism can enhance immune responses against tumors by activating CD8+ T cells and inhibiting vasculogenic mimicry, which synergizes with ICIs to improve treatment of ARID1A-deficient colorectal cancer. Significance: The arachidonic acid pathway is a metabolic vulnerability in ARID1A-deficient colorectal cancer that can be targeted with aspirin to suppress tumor growth and enhance sensitivity to immunotherapy, providing a promising therapeutic strategy.
富含AT序列相互作用结构域蛋白1A（ARID1A）是开关/蔗糖非发酵（SWI/SNF）复合物的核心成分，在约10%的结直肠癌中发生突变。虽然ARID1A缺陷与结直肠癌中增强的免疫活性相对应，但免疫检查点抑制剂（ICI）在这些肿瘤中的疗效有限。发现与结直肠癌中ARID1A缺陷相关的可靶向弱点可能会扩大患者的治疗选择。在本研究中，我们证明花生四烯酸（AA）代谢抑制剂通过增强CD8+T细胞活性和抑制血管生成拟态，与ICI在ARID1A缺陷的结直肠癌中发挥协同作用。使用ATAC-seq和ChIP-qPCR进行的表观遗传分析表明，ARID1A的缺失导致控制AA途径的关键酶PTGS1和PTGS2水平降低。PTGS1和PTGS2的低表达使ARID1A缺陷细胞对AA途径的剩余功能产生依赖。AA途径抑制剂阿司匹林选择性地抑制ARID1A缺陷的结直肠癌的生长，并且阿司匹林使缺乏ARID1A的肿瘤对免疫疗法敏感。总之，这些发现表明，阻断AA代谢可以通过激活CD8+T细胞和抑制血管生成拟态来增强针对肿瘤的免疫反应，这与ICI协同作用以改善ARID1A缺陷的结直肠癌的治疗。意义：花生四烯酸途径是ARID1A缺陷的结直肠癌中的一种代谢弱点，可用阿司匹林靶向以抑制肿瘤生长并增强对免疫疗法的敏感性，提供了一种有前景的治疗策略。
