结直肠癌免疫微环境对西妥昔单抗耐药的影响：机制与潜在应对策略
The Influence of the Colorectal Cancer Immune Microenvironment on Resistance to Cetuximab: Mechanisms and Potential Therapeutic Strategies
摘要: 结直肠癌(colorectal cancer, CRC)是全球常见的消化道恶性肿瘤之一，发病率位居第三，是癌症相关死亡的重要原因。传统以手术和化疗为主的综合治疗虽可延长患者生存，但总体预后仍不理想。近年来，以西妥昔单抗(cetuximab, CET)为代表的抗表皮生长因子受体(epidermal growth factor receptor, EGFR)单克隆抗体显著改善了RAS/RAF野生型转移性结直肠癌(metastatic CRC, mCRC)患者的结局。然而，无论是原发性耐药还是继发性耐药，均严重限制了CET的临床获益。既往研究多聚焦于肿瘤细胞内基因突变及下游通路激活，对肿瘤免疫微环境(tumor microenvironment, TME)在CET耐药中的作用关注有限。近年证据表明，M2型肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)、调节性T细胞(regulatory T cells, Tregs)及髓源性抑制细胞(myeloid-derived suppressor cells, MDSCs)等免疫抑制性细胞亚群，通过分泌IL-10、TGF-β等抑制性因子、上调免疫检查点分子以及重塑EGFR及其旁路信号通路，可削弱CET依赖的抗体依赖性细胞介导的细胞毒作用(antibody-dependent cellular cytotoxicity, ADCC)，并促进肿瘤免疫逃逸。此外，液体活检技术的快速发展，为动态监测RAS/RAF突变演化及免疫相关标志物变化提供了无创手段，有望用于评估免疫抑制性微环境状态及CET再挑战机会。本文综述了结直肠癌免疫微环境相关细胞在CET耐药中的作用机制，重点讨论TAMs、Tregs及MDSCs等亚群的关键分子通路，并总结液体活检及靶向免疫抑制性微环境的潜在应对策略，以期为mCRC的个体化联合治疗提供理论依据。
Abstract: Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract worldwide, ranking third in incidence and representing a major cause of cancer-related mortality. Although conventional multidisciplinary treatment centered on surgery and chemotherapy can prolong survival, the overall prognosis remains unsatisfactory. In recent years, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, represented by cetuximab (CET), have significantly improved outcomes in patients with RAS/RAF wild-type metastatic colorectal cancer (mCRC). However, both primary and acquired resistance substantially limit the clinical benefit of CET. Previous studies have mainly focused on genetic alterations within tumor cells and activation of downstream signaling pathways, while relatively little attention has been paid to the role of the tumor immune microenvironment (tumor microenvironment, TME) in CET resistance. Emerging evidence indicates that immunosuppressive cell subsets, such as M2-polarized tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs), can attenuate CET-dependent antibody-dependent cellular cytotoxicity (ADCC) and promote tumor immune escape by secreting inhibitory factors including IL-10 and TGF-β, upregulating immune checkpoint molecules, and reshaping EGFR and its bypass signaling pathways. In addition, the rapid development of liquid biopsy technologies provides a noninvasive approach for dynamically monitoring the evolution of RAS/RAF mutations and changes in immune-related biomarkers, which holds promise for evaluating the status of the immunosuppressive microenvironment and determining the optimal timing for CET rechallenge. This review summarizes the mechanisms by which immune microenvironment–related cellular components contribute to CET resistance in colorectal cancer, with a particular focus on key molecular pathways involving TAMs, Tregs, and MDSCs, and discusses potential strategies targeting the immunosuppressive microenvironment and incorporating liquid biopsy, with the aim of providing a theoretical basis for individualized combination therapy in patients with mCRC.
文章引用：叶唐毅, 龚瑾. 结直肠癌免疫微环境对西妥昔单抗耐药的影响：机制与潜在应对策略[J]. 临床医学进展, 2025, 15(12): 2612-2622. https://doi.org/10.12677/acm.2025.15123695

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