Cartwright Douglas, Kidd Andrew C, Ansel Sonam, Ascierto Maria Libera, Spiliopoulou Pavlina
School of Cancer Sciences, University of Glasgow, Bearsden, Glasgow G61 1QH, UK.
Beatson West of Scotland Cancer Centre,1053 Great Western Road, Glasgow G12 0YN, UK.
Int J Mol Sci. 2025 May 6;26(9):4393. doi: 10.3390/ijms26094393.
Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.
免疫检查点抑制剂已成为许多实体器官恶性肿瘤治疗的中流砥柱。与此同时，致癌驱动因子的识别和靶向治疗也迅速发展。致癌驱动因子改变的存在不仅可预测对靶向治疗的反应，还可调节免疫微环境并影响对免疫治疗的反应。将免疫检查点抑制剂与靶向药物联合使用是一种有吸引力的治疗选择，但重叠的毒性特征可能会限制某些联合治疗的临床应用。此外，越来越多的证据表明存在共同的耐药机制，这些机制会改变靶向治疗后使用免疫治疗时的反应。了解致癌驱动因子、靶向治疗和免疫检查点抑制剂反应之间的这种复杂相互作用，对于在正确的时间为正确的患者选择正确的治疗方法至关重要。在这篇综述中，我们总结了四种常见致癌改变对免疫检查点抑制剂反应、联合治疗以及共同耐药机制存在的影响的临床前和临床证据。我们强调了常见的耐药机制以及开展更多研究联合治疗和序贯治疗的随机试验的必要性。
