Cheng Xiaoliang, Wang Peixing, Lyu Hongqiang, Lee Yonghyun, Yoon Juyoung, Dong Haiyan
Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
College of Pharmacy, Ewha Womans University, Seoul 03760, South Korea.
Cancer Drug Resist. 2025 Sep 2;8:46. doi: 10.20517/cdr.2025.132. eCollection 2025.
Immunotherapy has emerged as a major therapeutic strategy for cancer; however, immunotherapy resistance remains a significant challenge. Hypoxia, a key hallmark of the tumor microenvironment resulting from the imbalance between the high oxygen demand of rapidly proliferating cancer cells and the limited supply from abnormal blood vessels, plays a central role in driving immunotherapy resistance. Hypoxia-inducible factor-1α (HIF-1α) and its downstream signaling pathways contribute to this resistance by promoting macrophage polarization toward the protumorigenic M2 phenotype, inducing T cell exhaustion, facilitating immune evasion, enhancing angiogenesis, and activating other resistance mechanisms. The review highlights the mechanisms by which hypoxia regulates resistance to immunotherapy and provides a comprehensive overview of nanotechnology-based strategies designed to counteract hypoxia-induced resistance. Finally, the prospects and challenges of translating nanomedicine-based drug delivery systems into clinical practice for overcoming immunotherapy resistance are outlined.
免疫疗法已成为癌症的主要治疗策略；然而，免疫疗法耐药性仍然是一个重大挑战。缺氧是肿瘤微环境的一个关键特征，它是由快速增殖的癌细胞对氧气的高需求与异常血管的有限供应之间的不平衡所导致的，在驱动免疫疗法耐药性方面起着核心作用。缺氧诱导因子-1α（HIF-1α）及其下游信号通路通过促进巨噬细胞向促肿瘤的M2表型极化、诱导T细胞耗竭、促进免疫逃逸、增强血管生成以及激活其他耐药机制，从而导致这种耐药性。本文综述强调了缺氧调节免疫疗法耐药性的机制，并全面概述了旨在对抗缺氧诱导耐药性的基于纳米技术的策略。最后，概述了将基于纳米医学的药物递送系统转化为临床实践以克服免疫疗法耐药性的前景和挑战。
