Dai Yuening, Tian Xueqi, Ye Xuanting, Gong Yabin, Xu Ling, Jiao Lijing
Department of Oncology I, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Institute of Translational Cancer Research for Integrated Chinese and Western Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Cancer Drug Resist. 2024 Dec 16;7:52. doi: 10.20517/cdr.2024.166. eCollection 2024.
Primary and secondary resistance to immune checkpoint blockade (ICB) reduces its efficacy. The mechanisms underlying immunotherapy resistance are highly complex. In non-small cell lung cancer (NSCLC), these mechanisms are primarily associated with the loss of programmed cell death-ligand 1 (PD-L1) expression, genetic mutations, circular RNA axis and transcription factor regulation, antigen presentation disorders, and dysregulation of signaling pathways. Additionally, alterations in the tumor microenvironment (TME) play a pivotal role in driving immunotherapy resistance. Primary resistance is mainly attributed to TME alterations, including mutations and co-mutations, modulation of T cell infiltration, enrichment of M2 tumor-associated macrophages (M2-TAMs) and mucosal-associated invariant T (MAIT) cells, vascular endothelial growth factor (VEGF), and pulmonary fibrosis. Acquired resistance mainly stems from changes in cellular infiltration patterns leading to "cold" or "hot" tumors, altered interferon (IFN) signaling pathway expression, involvement of extracellular vesicles (EVs), and oxidative stress responses, as well as post-treatment gene mutations and circadian rhythm disruption (CRD). This review presents an overview of various mechanisms underlying resistance to ICB, elucidates the alterations in the TME during primary, adaptive, and acquired resistance, and discusses existing strategies for overcoming ICB resistance.
对免疫检查点阻断（ICB）的原发性和继发性耐药性会降低其疗效。免疫治疗耐药的潜在机制非常复杂。在非小细胞肺癌（NSCLC）中，这些机制主要与程序性细胞死亡配体1（PD-L1）表达缺失、基因突变、环状RNA轴和转录因子调控、抗原呈递障碍以及信号通路失调有关。此外，肿瘤微环境（TME）的改变在驱动免疫治疗耐药中起关键作用。原发性耐药主要归因于TME改变，包括突变和共突变、T细胞浸润的调节、M2肿瘤相关巨噬细胞（M2-TAM）和黏膜相关恒定T细胞（MAIT）的富集、血管内皮生长因子（VEGF）以及肺纤维化。获得性耐药主要源于细胞浸润模式的改变导致“冷”或“热”肿瘤、干扰素（IFN）信号通路表达改变、细胞外囊泡（EV）的参与以及氧化应激反应，以及治疗后基因突变和昼夜节律紊乱（CRD）。本综述概述了ICB耐药的各种潜在机制，阐明了原发性、适应性和获得性耐药期间TME的改变，并讨论了克服ICB耐药的现有策略。
