Immune checkpoint blockade (ICB) therapy works by inhibiting suppressive checkpoints that become upregulated after T cell activation, like PD-1/PD-L1 and CTLA-4. While the initial FDA approvals of ICB have revolutionized cancer therapies and fueled a burgeoning immuno-oncology field, more recent clinical development of new agents has been slow. Here, focusing on lung cancer, we review the latest research uncovering tumor cell intrinsic and extrinsic ICB resistance mechanisms as major hurdles to treatment efficacy and clinical progress. These include genomic and non-genomic tumor cell alterations, along with host and microenvironmental factors like the microbiome, metabolite accumulation, and hypoxia. Together, these factors can cooperate to promote immunosuppression and ICB resistance. Opportunities to prevent resistance are constantly evolving in this rapidly expanding field, with the goal of moving toward personalized immunotherapeutic regimens.

中文翻译：

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肺癌的免疫检查点阻断抵抗：新兴机制和治疗机会


免疫检查点阻断 (ICB) 疗法通过抑制 T 细胞激活后上调的抑制性检查点（如 PD-1/PD-L1 和 CTLA-4）发挥作用。虽然 FDA 最初批准 ICB 彻底改变了癌症疗法并推动了免疫肿瘤学领域的蓬勃发展，但最近新药的临床开发进展缓慢。在这里，我们重点关注肺癌，回顾了最新的研究，揭示了肿瘤细胞内在和外在的 ICB 耐药机制是治疗效果和临床进展的主要障碍。这些包括基因组和非基因组肿瘤细胞的改变，以及宿主和微环境因素，如微生物组、代谢物积累和缺氧。这些因素共同作用，促进免疫抑制和 ICB 耐药。在这个快速扩张的领域，预防耐药性的机会不断变化，目标是走向个性化免疫治疗方案。