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<p>Chemokines and their receptors play central regulatory roles in mediating the migration and functional modulation of diverse immune subsets, thereby shaping the immunosuppressive tumor microenvironment. This review systematically summarizes the key mechanisms of paired chemokine-receptor axes in tumor immune escape, with a focus on their regulatory networks and pro-escape mechanisms across multiple immune cells. Studies reveal that receptors such as CCR4, CCR5, CCR8, CXCR2, and CXCR4 facilitate the infiltration of immunosuppressive cells, while impaired signaling through receptors like CXCR3 and CXCR6 leads to effector T cell exhaustion or mislocalization. Preclinical and clinical evidence demonstrate that targeting chemokine receptors, for example, mogamulizumab (anti-CCR4) and plerixafor (anti-CXCR4), can effectively remodel the tumor immune microenvironment and enhance anti-tumor immune responses. This review further proposes a “3D-targeting strategy”: Decrease immunosuppressive cell recruitment, develop effector cell response, and dismantle physical barriers. It also explores potential combination therapeutic approaches of immune checkpoint inhibitors, simultaneous multi-receptor blockade, radiotherapy, and chemotherapy. Despite challenges including systemic redundancy, tumor heterogeneity, and off-target effects, future research holds promise for achieving precise and personalized chemokine-receptor-targeted therapies through cutting-edge technologies like single-cell and spatial omics, artificial intelligence-driven prediction, microenvironment-specific delivery systems, and organoid models. In conclusion, targeting chemokines and their receptors represents a promising strategy for reprogramming the immunosuppressive microenvironment and overcoming immune escape, offering new avenues for advancing cancer immunotherapy.</p>

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Chemokines and chemokine receptors: the key regulators of tumor microenvironment

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月8日

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  • Huan He,
  • Pengyuan Yang,
  • Yanan Gao

摘要

Chemokines and their receptors play central regulatory roles in mediating the migration and functional modulation of diverse immune subsets, thereby shaping the immunosuppressive tumor microenvironment. This review systematically summarizes the key mechanisms of paired chemokine-receptor axes in tumor immune escape, with a focus on their regulatory networks and pro-escape mechanisms across multiple immune cells. Studies reveal that receptors such as CCR4, CCR5, CCR8, CXCR2, and CXCR4 facilitate the infiltration of immunosuppressive cells, while impaired signaling through receptors like CXCR3 and CXCR6 leads to effector T cell exhaustion or mislocalization. Preclinical and clinical evidence demonstrate that targeting chemokine receptors, for example, mogamulizumab (anti-CCR4) and plerixafor (anti-CXCR4), can effectively remodel the tumor immune microenvironment and enhance anti-tumor immune responses. This review further proposes a “3D-targeting strategy”: Decrease immunosuppressive cell recruitment, develop effector cell response, and dismantle physical barriers. It also explores potential combination therapeutic approaches of immune checkpoint inhibitors, simultaneous multi-receptor blockade, radiotherapy, and chemotherapy. Despite challenges including systemic redundancy, tumor heterogeneity, and off-target effects, future research holds promise for achieving precise and personalized chemokine-receptor-targeted therapies through cutting-edge technologies like single-cell and spatial omics, artificial intelligence-driven prediction, microenvironment-specific delivery systems, and organoid models. In conclusion, targeting chemokines and their receptors represents a promising strategy for reprogramming the immunosuppressive microenvironment and overcoming immune escape, offering new avenues for advancing cancer immunotherapy.