Tumor microenvironment chemokine network: from immune escape mechanisms to multi-dimensional targeting strategies

A comprehensive review published in Volume 2, article number 24 of the journal Immunity & Inflammation on May 8, 2026, by the team of Professor Pengyuan Yang and Professor Yanan Gao at the Institute of Biophysics, Chinese Academy of Sciences, systematically delineates the chemokine and chemokine receptor network within the tumor microenvironment. The article summarizes current knowledge on how chemokine signaling controls immune cell trafficking and function in cancer, and introduces a novel "3D" targeting framework—Decrease, Develop, Dismantle—to guide the development of precision combination immunotherapies.

Tumor immune evasion is a central driver of cancer initiation, progression, and metastasis. This process involves the remodeling of the local microenvironment into a complex immunosuppressive barrier that resists anti-tumor immune responses. Chemokines and their receptors function as a sophisticated "molecular navigation system" for remodeling the tumor microenvironment (TME), precisely controlling the migration and functional states of diverse immune subsets.

The review constructs a panoramic view of chemokine-receptor interactions within the TME. Unlike traditional studies that focus on isolated chemokine axes and specific immune cell types, this work treats the chemokine system as a spatiotemporally encoded network. Tumor cells secrete multiple chemokines to establish spatial gradients that guide the directed recruitment of immunosuppressive cells—including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs)—while simultaneously repelling or exhausting effector T cells and natural killer (NK) cells. This coordinated chemokine signaling collectively builds a local immunosuppressive barrier that resists anti-tumor immunity.

Based on this systematic analysis, the authors propose a 3D multi-dimensional targeting strategy: Decrease refers to reducing recruitment of suppressive cells by antagonizing receptors such as CCR4, CCR8, CCR2, and CXCR2, thereby blocking Treg, MDSC, and TAM infiltration into the tumor microenvironment.

Develop involves enhancing effector cell function by agonizing receptors including CXCR3, CXCR6, and XCR1, to promote the recruitment, survival, and cytotoxic activity of effector T cells, NK cells, and conventional type 1 dendritic cells (cDC1).

Dismantle focuses on breaking down physical and signaling barriers by antagonizing receptors such as CXCR4, thereby disrupting the CXCL12-formed "immune-privileged" niche that physically sequesters effector cells away from the tumor.

Although targeting chemokine receptors to remodel the TME has tremendous potential, clinical translation faces three major challenges. First, the high redundancy and compensatory mechanisms of the chemokine system mean that blocking a single target often leads to upregulation of alternative ligands or receptors by the tumor. Second, off-target toxicity remains a concern, as exemplified by anti-CCR4 therapies that also deplete CCR4-expressing central memory CD8⁺ T cells in the periphery. Third, tumor heterogeneity—across spatial regions, temporal phases, and cellular subpopulations—creates a moving target for chemokine-directed interventions.

“Future breakthroughs will require a shift from empirical single-target attempts to network-controlled precision intervention,” the authors pointed out. The review identifies key directions: integrating single-cell and spatial multi-omics to decode chemokine communication topology within the TME; applying artificial intelligence to guide highly selective drug design; developing microenvironment-responsive delivery systems for in situ release; and using patient-derived organoid and organ-on-a-chip models to prospectively validate combination strategies. “The convergence of these approaches holds promise for translating chemokine-targeted therapies into clinical reality,” the authors outlined.

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Reference
DOI: 10.1007/s44466-026-00038-0

About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.

Website: https://link.springer.com/journal/44466

About Professor Pengyuan Yang from Chinese Academy of Sciences, China
Prof. Yang is a Principal Investigator at the State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences. He has received numerous awards including the Yao Kaitai Outstanding Scientist Achievement Award and the Meiji Life Science Award. His research focuses on hepatitis B virus infection and immune regulatory mechanisms.

About Professor Yanan Gao from Chinese Academy of Sciences, China
Prof. Gao is a Principal Investigator at the State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences. Her research focuses on hepatitis B virus oncogenic mechanisms and immune microenvironment regulation.

About Ms Huan He from Chinese Academy of Sciences, China
Ms He is a graduate student at the State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences. Her research focuses on targeted intervention of the hepatitis B virus immune microenvironment.

Funding information
This work was supported by the National Natural Science Foundation of China (82225037, 92374206 to P.Y., 82573006 to Y.G.), the National Key R&D Program of China (2022YFA1303602 to P.Y.), the Strategic Priority Research Program of CAS (XDB1000000 to Y.G.), the Beijing Municipal Science & Technology Commission, Administrative Commission of Zhongguancun Science Park (Z221100007922030 to Y.G.).