Zheng Zhuangzhuang, Bian Chenbin, Wang Huanhuan, Su Jing, Meng Lingbin, Xin Ying, Jiang Xin
Department of Radiation Oncology, the First Hospital of Jilin University, Changchun China.
Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, Changchun, China.
Ther Adv Med Oncol. 2022 Nov 19;14:17588359221138383. doi: 10.1177/17588359221138383. eCollection 2022.
Immunotherapy has been used in the clinical treatment of colorectal cancer (CRC); however, most patients fail to achieve satisfactory survival benefits. Biomarkers with high specificity and sensitivity are being increasingly developed to predict the efficacy of CRC immunotherapy. In addition to DNA alteration markers, such as microsatellite instability/mismatch repair and tumor mutational burden, immune cell infiltration and immune checkpoints (ICs), epigenetic changes and no-coding RNA, and gut microbiomes all show potential predictive ability. Recently, the hypoxic tumor microenvironment (TME) has been identified as a key factor mediating CRC immune evasion and resistance to treatment. Hypoxia-inducible factor-1α is the central transcription factor in the hypoxia response that drives the expression of a vast number of survival genes by binding to the hypoxia response element in cancer and immune cells in the TME. Hypoxia regulates angiogenesis, immune cell infiltration and activation, expression of ICs, and secretion of various immune molecules in the TME and is closely associated with the immunotherapeutic efficacy of CRC. Currently, various agents targeting hypoxia have been found to improve the TME and enhance the efficacy of immunotherapy. We reviewed current markers commonly used in CRC to predict therapeutic efficacy and the mechanisms underlying hypoxia-induced angiogenesis and tumor immune evasion. Exploring the mechanisms by which hypoxia affects the TME will assist the discovery of new immunotherapeutic predictive biomarkers and development of more effective combinations of agents targeting hypoxia and immunotherapy.
免疫疗法已被用于结直肠癌（CRC）的临床治疗；然而，大多数患者未能获得令人满意的生存益处。目前正在越来越多地开发具有高特异性和敏感性的生物标志物，以预测CRC免疫疗法的疗效。除了DNA改变标志物，如微卫星不稳定性/错配修复和肿瘤突变负荷外，免疫细胞浸润和免疫检查点（ICs）、表观遗传变化和非编码RNA以及肠道微生物群均显示出潜在的预测能力。最近，缺氧肿瘤微环境（TME）已被确定为介导CRC免疫逃逸和治疗抵抗的关键因素。缺氧诱导因子-1α是缺氧反应中的核心转录因子，它通过与TME中癌细胞和免疫细胞中的缺氧反应元件结合，驱动大量生存基因的表达。缺氧调节TME中的血管生成、免疫细胞浸润和激活、ICs的表达以及各种免疫分子的分泌，并且与CRC的免疫治疗疗效密切相关。目前，已发现多种靶向缺氧的药物可改善TME并增强免疫治疗的疗效。我们综述了目前CRC中常用的预测治疗疗效的标志物以及缺氧诱导血管生成和肿瘤免疫逃逸的潜在机制。探索缺氧影响TME的机制将有助于发现新的免疫治疗预测生物标志物，并开发更有效的靶向缺氧与免疫治疗的联合用药方案。
