The CCL2/CCR2 axis in irradiated tumors: orchestrating immune recruitment and microenvironment remodeling

Abstract

Radiotherapy (RT) is a cornerstone of solid tumor treatment, but its capacity to reshape the tumor microenvironment (TME) also has a less favorable consequences: acquired radioresistance, which can limit durable systemic antitumor immunity. Within this remodeling process, the CCL2/CCR2 axis has emerged as a key organizer of the immunosuppressive network. This review summarizes the transcriptional regulation and microenvironmental effects of the CCL2/CCR2 axis in response to radiation-induced stress. Evidence indicates that RT triggers DNA damage and a burst of reactive oxygen species (ROS), which in turn activate the ATM/NF-κB and STAT3 pathways. These signals induce surviving tumor cells and stromal components, such as cancer-associated fibroblasts (CAFs), to secrete CCL2 persistently and robustly. Elevated CCL2 then recruits peripheral monocytes and immature myeloid cells into the TME, where they differentiate into tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Through the release of pro-tumorigenic factors, Arg-1, and nitric oxide, these myeloid populations not only drive effector T cell exhaustion but also promote abnormal angiogenesis and tissue fibrosis. These structural changes create physical barriers that hinder T cell infiltration, together shaping an immunosuppressive microenvironment. Importantly, the immunological effects of RT are schedule-dependent: conventional fractionated RT may sustain chronic CCL2 production and myeloid recruitment, whereas hypofractionated RT or stereotactic body radiation therapy may differentially regulate cGAS/STING/type Ⅰ interferon signaling, Trex1 induction, and CCL2/CCR2-mediated myeloid suppression. The review also discusses current clinical combination strategies, with attention to triple therapy that integrates CCL2/CCR2 blockade, RT, and immune checkpoint inhibitors (ICIs). In this approach, RT promotes antigen release, CCR2 inhibition limits myeloid and stromal barriers, and ICIs restore exhausted T cell function. Overall, targeting the CCL2/CCR2 axis offers a way to address bottlenecks in local control and may help RT function as an in situ vaccine that supports lasting, systemic antitumor immunity.

Keywords

Radiotherapy / Tumor microenvironment / CCL2/CCR2 axis / Tumor-associated macrophage / Immune checkpoint inhibitor / Radiation-induced fibrosis

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Funding

Shenzhen Science and Technology Program(JCYJ20240813142112017)

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