Chemokines, acting as "traffic controllers" in the tumor microenvironment, regulate immune cell infiltration and local immunity. This review summarizes the chemokine expression profiles in tumors, their diverse roles in pro- and anti-tumor immunity, current targeting strategies (inhibition, delivery, engineering), and synergistic potential ability with other immunotherapies. Despite challenges, targeting the chemokine receptor axis holds great promise for reprogramming the tumor microenvironment and advancing precision cancer therapy.
Chemokines, a critical class of cell-signaling molecules, function as essential “traffic controllers” within the tumor microenvironment (TME). By establishing precise concentration gradients, they serve as invisible signposts that guide diverse immune cells, including T cells, natural killer cells, monocytes/macrophages, and dendritic cells, to migrate across complex tissue barriers and infiltrate tumor lesions in a directional manner. In addition to regulating immune cell trafficking, chemokines directly modulate immune cell activation, proliferation, and functional states through interactions with their cognate receptors, thereby shaping the dynamic balance between immune activation and immunosuppression in tumors. Given their central role in tumor immunity, the chemokine–chemokine receptor signaling axis has emerged as a promising therapeutic target in cancer immunotherapy.
Within the TME, this signaling network not only regulates key biological behaviors of tumor cells, including proliferation, apoptosis, and epithelial–mesenchymal transition, but also shapes the immune landscape by recruiting immune cell populations with distinct phenotypes. Through these mechanisms, chemokines influence tumor initiation, progression, invasion, and metastasis. Therefore, comprehensive characterization of the expression patterns, regulatory networks, and spatiotemporal heterogeneity of the chemokine system in the TME is of substantial importance for understanding tumor immunobiology and for developing more effective immunotherapeutic strategies capable of eliciting durable anti-tumor immune responses.
In a recent review article, made available online on March 11, 2026, in the Chinese Medical Journal , researchers from China—including Professors Yong Zhao and Hezhe Lu from the Chinese Academy of Sciences and Professor Guiying Wang from Hebei Medical University—systematically summarize the expression profiles of chemokines across diverse human malignancies, their complex immunomodulatory functions, and emerging therapeutic strategies targeting these molecules.
The researchers highlight several intervention approaches designed to modulate aberrantly activated or highly expressed chemokine–chemokine receptor axes in different tumor types. First, small-molecule inhibitors or neutralizing antibodies can block immunosuppressive chemokine signaling (for example, CCL2 or CXCL12), thereby alleviating immunosuppression in the TME and restoring the activity of effector immune cells.
Second, advanced delivery platforms, including oncolytic viruses and antibody–drug conjugates, can locally introduce immunostimulatory chemokines (such as CXCL9, CXCL10, or CCL5) into tumors to enhance effector immune cell recruitment and convert immunologically “cold” tumors into “hot” tumors. Third, genetic engineering approaches enable the modification of chimeric antigen receptor (CAR)-T cells or T cell receptor (TCR)-T cells to overexpress specific chemokine receptors (for example, CXCR2 or CXCR3), thereby improving their tumor homing and infiltration efficiency.
Furthermore, combining chemokine-modulating strategies with other immunotherapeutic modalities has demonstrated considerable synergistic potential. For instance, integration with tumor vaccines can enhance antigen-specific immune responses; combination with immune checkpoint inhibitors, such as anti-PD-1 or anti-PD-L1 antibodies, may overcome therapeutic resistance associated with insufficient immune cell infiltration; and integration with adoptive cell therapies can improve the survival, expansion, and anti-tumor activity of transferred immune cells in vivo, while potentially promoting the formation of tertiary lymphoid structures (TLS) that support sustained anti-tumor immunity.
This article also discusses potential strategies to modulate chemokine expression through epigenetic regulation, including histone modifications and DNA methylation, which may provide new opportunities for developing chemokine-targeted therapeutics. Nevertheless, despite the considerable promise of chemokine-based interventions, several challenges remain. These include the complexity and redundancy of chemokine networks, substantial inter-tumoral and inter-patient heterogeneity, and potential off-target effects or toxicities associated with systemic administration. Future studies are therefore required to elucidate the precise regulatory mechanisms governing chemokine signaling in tumor immunity, to develop more specific and safer targeting strategies, and to validate their efficacy through well-designed clinical trials.
In summary, targeting the chemokine–chemokine receptor axis offers a promising strategy for reprogramming the tumor immune microenvironment and overcoming immune tolerance. As research into the chemokine system continues to advance, chemokine-based approaches are expected to become an important component of next-generation integrated cancer immunotherapies, ultimately contributing to more precise and effective treatment strategies for patients with cancer.
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About Yang Zhao
Institute of Zoology, Chinese Academy of Sciences
Assistant Research Professor
Research Interests: Development of innate immune cells and their functions in diseases such as cancer.
Xueqian Wang
Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
Postdoctoral Fellow
Research Interests: Protein structure and function.
Tong Lei
Research Interests: Mechanisms underlying the origin and development of innate immune cells.
Guiying Wang
General Surgery Department, the Second Hospital of Hebei Medical University; General Surgery Department, the Fourth Hospital of Hebei Medical University
Professor
Research Interests: Gastrointestinal Tract Tumors, tumor immunotherapy
Hezhe Lu
Research Professor, Overseas High-Level Young Talent
Research Interests: Focusing on the role of cellular heterogeneity in tumor initiation and progression; Identification of rare drug-resistant tumor cells and design of targeted drugs; Fate trajectories of cells following oncogenic mutations.
Yong Zhao
Faculty of Synthetic Biology, Shenzhen University of Advanced Technology; Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Chair Professor, National Distinguished Young Scholar
Research Interests: Transplantation immunology, immune tolerance induction, application of immunosuppressive immune cells, thymic development, and macrophage biology.
Funding information
This work was supported by grants from Shenzhen Medical Research Fund (No. B2302030), the National Natural Science Foundation of China for Key Program (Nos. 32330037 and 81802846), and the National Key Research and Development Program of China (No. 2023YFA0915000).
Chinese Medical Journal
Literature review
Cells
Exploiting the chemokine–chemokine receptor axis: Emerging immunotherapeutic paradigms for solid tumor microenvironment reprogramming
11-Mar-2026
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