Immune checkpoint blockade (ICB) induces a remarkable and durable response in a subset of cancer patients. However, most patients exhibit either primary or acquired resistance to ICB. This resistance arises from a complex interplay of diverse dynamic mechanisms within the tumor microenvironment (TME). These mechanisms include genetic, epigenetic, and metabolic alterations that prevent T cell trafficking to the tumor site, induce immune cell dysfunction, interfere with antigen presentation, drive heightened expression of coinhibitory molecules, and promote tumor survival after immune attack. The TME worsens ICB resistance through the formation of immunosuppressive networks via immune inhibition, regulatory metabolites, and abnormal resource consumption. Finally, patient lifestyle factors, including obesity and microbiome composition, influence ICB resistance. Understanding the heterogeneity of cellular, molecular, and environmental factors contributing to ICB resistance is crucial to develop targeted therapeutic interventions that enhance the clinical response. This comprehensive overview highlights key mechanisms of ICB resistance that may be clinically translatable.Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

中文翻译：

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超越障碍：揭示免疫治疗耐药机制

免疫检查点阻断 (ICB) 在一部分癌症患者中引起显着且持久的反应。然而，大多数患者表现出对 ICB 的原发性或获得性耐药。这种耐药性源于肿瘤微环境（TME）内多种动态机制的复杂相互作用。这些机制包括遗传、表观遗传和代谢改变，阻止 T 细胞运输到肿瘤部位，诱导免疫细胞功能障碍，干扰抗原呈递，驱动共抑制分子表达增加，并促进免疫攻击后肿瘤的存活。 TME 通过免疫抑制、调节代谢物和异常资源消耗形成免疫抑制网络，从而恶化 ICB 耐药性。最后，患者的生活方式因素，包括肥胖和微生物组组成，会影响 ICB 耐药性。了解导致 ICB 耐药的细胞、分子和环境因素的异质性对于开发增强临床反应的针对性治疗干预措施至关重要。这份全面的概述强调了可能在临床上可转化的 ICB 耐药性的关键机制。《免疫学年度评论》第 42 卷的预计最终在线出版日期为 2024 年 4 月。请参阅 http://www.annualreviews.org/page/journal/pubdates修订后的估计。