Zhang Chenyue, Zhang Chenxing, Wang Haiyong
Department of Integrated Therapy, Fudan University Shanghai Cancer Center, Shanghai Medical College, Shanghai, China.
Department of Nephrology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Lett. 2023 May 28;562:216182. doi: 10.1016/j.canlet.2023.216182. Epub 2023 Apr 17.
Cancer treatment has been advanced with the advent of immune checkpoint inhibitors (ICIs) exemplified by anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) drugs. Patients have reaped substantial benefit from ICIs in many cancer types. However, few patients benefit from ICIs whereas the vast majority undergoing these treatments do not obtain survival benefit. Even for patients with initial responses, they may encounter drug resistance in their subsequent treatments, which limits the efficacy of ICIs. Therefore, a deepening understanding of drug resistance is critically important for the explorations of approaches to reverse drug resistance and to boost ICI efficacy. In the present review, different mechanisms of ICI resistance have been summarized according to the tumor intrinsic, tumor microenvironment (TME) and host classifications. We further elaborated corresponding strategies to battle against such resistance accordingly, which include targeting defects in antigen presentation, dysregulated interferon-γ (IFN-γ) signaling, neoantigen depletion, upregulation of other T cell checkpoints as well as immunosuppression and exclusion mediated by TME. Moreover, regarding the host, several additional approaches that interfere with diet and gut microbiome have also been described in reversing ICI resistance. Additionally, we provide an overall glimpse into the ongoing clinical trials that utilize these mechanisms to overcome ICI resistance. Finally, we summarize the challenges and opportunities that needs to be addressed in the investigation of ICI resistance mechanisms, with the aim to benefit more patients with cancer.
随着以抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）、抗程序性细胞死亡蛋白1（PD-1）和程序性细胞死亡配体1（PD-L1）药物为代表的免疫检查点抑制剂（ICI）的出现，癌症治疗取得了进展。许多癌症类型的患者已从ICI中获得了巨大益处。然而，只有少数患者从ICI中获益，而绝大多数接受这些治疗的患者并未获得生存益处。即使是初始有反应的患者，在后续治疗中也可能会遇到耐药性，这限制了ICI的疗效。因此，深入了解耐药性对于探索逆转耐药性和提高ICI疗效的方法至关重要。在本综述中，根据肿瘤内在因素、肿瘤微环境（TME）和宿主分类总结了ICI耐药的不同机制。我们进一步阐述了相应的对抗此类耐药性的策略，包括针对抗原呈递缺陷、失调的干扰素-γ（IFN-γ）信号传导、新抗原耗竭、其他T细胞检查点上调以及TME介导的免疫抑制和排除。此外，关于宿主，还描述了几种通过干扰饮食和肠道微生物群来逆转ICI耐药性的额外方法。此外，我们全面介绍了利用这些机制克服ICI耐药性的正在进行的临床试验。最后，我们总结了在ICI耐药机制研究中需要解决的挑战和机遇，旨在使更多癌症患者受益。
