Rahimi Ali, Baghernejadan Zeinab, Hazrati Ali, Malekpour Kosar, Samimi Leila Nejatbakhsh, Najafi Alireza, Falak Reza, Khorramdelazad Hossein
Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Biomed Pharmacother. 2025 May;186:118014. doi: 10.1016/j.biopha.2025.118014. Epub 2025 Mar 28.
Colorectal cancer (CRC) is still one of the leading causes of cancer deaths worldwide. Even though there has been progress in cancer immunotherapy, the results of applying immune checkpoint inhibitors (ICIs) have been unsatisfactory, especially in microsatellite stable (MSS) CRC. Single-agent ICIs that target programmed cell death-1 (PD-1)/ PD-L1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell Ig- and mucin-domain-containing molecule-3 (TIM-3), and lymphocyte activation gene (LAG)-3 have emerged as having specific benefits. However, many primary and secondary resistance mechanisms are available in the tumor microenvironment (TME) that prevent it from happening. Combination strategies, such as the use of anti-PD-1 and anti-CTLA-4, can be effective in overcoming these resistance pathways, but toxicities remain a significant concern. Moreover, ICIs have been integrated with various treatment modalities, including chemotherapy, radiotherapy, antibiotics, virotherapy, polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, and heat shock protein 90 (HSP90) inhibitors. The outcomes observed in both preclinical and clinical settings have been encouraging. Interestingly, manipulating gut microbiota via fecal microbiota transplantation (FMT) has been identified as a new strategy to increase the efficacy of immunotherapy in CRC patients. Therefore, integrating ICIs with other treatment approaches holds promise in enhancing the prognosis of CRC patients. This review focuses on the unmet need for new biomarkers to select patients for combination therapies and the ongoing work to overcome resistance and immune checkpoint blockade.
结直肠癌（CRC）仍是全球癌症死亡的主要原因之一。尽管癌症免疫疗法取得了进展，但应用免疫检查点抑制剂（ICI）的结果并不理想，尤其是在微卫星稳定（MSS）的CRC中。靶向程序性细胞死亡蛋白1（PD-1）/PD-L1、细胞毒性T淋巴细胞相关蛋白4（CTLA-4）、含T细胞免疫球蛋白和粘蛋白结构域分子3（TIM-3）以及淋巴细胞激活基因（LAG）-3的单克隆ICI已显示出特定的益处。然而，肿瘤微环境（TME）中存在许多原发性和继发性耐药机制，阻碍了ICI发挥作用。联合策略，如使用抗PD-1和抗CTLA-4，可以有效克服这些耐药途径，但毒性仍然是一个重大问题。此外，ICI已与多种治疗方式相结合，包括化疗、放疗、抗生素、病毒疗法、聚腺苷二磷酸核糖聚合酶（PARP）抑制剂和热休克蛋白90（HSP90）抑制剂。临床前和临床研究中观察到的结果令人鼓舞。有趣的是，通过粪便微生物群移植（FMT）操纵肠道微生物群已被确定为提高CRC患者免疫治疗疗效的新策略。因此，将ICI与其他治疗方法相结合有望改善CRC患者的预后。本综述重点关注选择联合治疗患者的新生物标志物的未满足需求，以及克服耐药性和免疫检查点阻断的正在进行的工作。
