Approximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting. This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs. In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant ‘window-of-opportunity’ trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples. Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance.

大约 15% 的局部晚期结直肠癌 （CRC） 存在 DNA 错配修复缺陷 （dMMR），导致微卫星高度不稳定和肿瘤突变负荷高。这些癌症在转移性情况下通常对免疫检查点抑制剂 （ICI） 治疗敏感。这种敏感性在局部晚期疾病中似乎更为明显，在正在进行的涉及 dMMR 直肠癌患者的临床试验中，器官保留已成为一个现实的目标。相比之下，具有熟练 DNA 错配修复 （pMMR） 的转移性 CRC 通常对 ICI 耐药，尽管一部分局部晚期 pMMR 肿瘤似乎对 ICI 高度敏感。在本综述中，我们描述了当前和新兴的临床证据，支持在 dMMR 和 pMMR CRC 患者中使用新辅助 ICIs，以及这种方法的潜在优势（基于生物学原理）。我们讨论了如何利用新辅助“机会之窗”试验来推进生物标志物的发现，并概述了对 ICI 反应的潜在预测生物标志物，探讨了在活检衍生样本中评估此类生物标志物时面临的挑战。最后，我们描述了如何利用这些发现来推动一种合理的方法，在 pMMR CRC 患者中试验新的免疫治疗策略，最终目标是根除疾病和产生长期免疫监测。