Radiation-induced CD200⁺ tumor-associated macrophages suppress eosinophil-mediated antitumor immunity through CD200R signaling in hepatocellular carcinoma.

Authors

Kun Li, Siqi Li, Dongbo Qiu, Xiusheng Qiu, Haoyuan Yu, Yi Xiong, Wei Liang, Zhixing Liang, Shuqun Cheng, Hua Li, Yunfei Qin, Yang Yang, Linsen Ye

Published in

Cellular & molecular immunology. Aug 13, 2026. Epub Aug 13, 2026.

Abstract

Radiotherapy elicits dual immunomodulatory effects in cancer, activating antitumor immunity while paradoxically inducing immunosuppression, which limits therapeutic efficacy. The molecular pathways mediating postradiation immune escape in hepatocellular carcinoma (HCC) remain poorly defined. Here, we elucidate a previously uncharacterized mechanism whereby radiotherapy drives the accumulation of CD200⁺ tumor-associated macrophages (TAMs) that suppress eosinophil-mediated antitumor immunity in patients with HCC. Through single-cell RNA sequencing of postradiotherapy HCC specimens, we demonstrated that radiation-induced DNA damage activated the cytosolic DNA-sensing STING pathway in TAMs, triggering NF-κB-dependent CD200 upregulation independent of canonical type I interferon signaling. These radiation-induced CD200⁺ TAMs exhibited an immunosuppressive phenotype and correlated with adverse clinical outcomes in HCC patients. Mechanistically, CD200⁺ TAMs established an immunosuppressive axis by recruiting CCR1⁺ eosinophils through CCL3-mediated chemotaxis, subsequently inhibiting their antitumor functions via CD200-CD200R engagement. This interaction comprehensively suppressed NF-κB activation in eosinophils, impaired their antigen-presenting capacity and Th2 cytokine secretion and abrogated their ability to support CD8⁺ T-cell-mediated cytotoxicity. Therapeutic blockade of CD200R following radiotherapy restored eosinophil effector functions, promoted central memory T-cell formation, and significantly enhanced tumor control across multiple preclinical HCC models. Remarkably, CD200R antagonism sensitized PD-1-refractory "cold" tumors to radioimmunotherapy combinations, overcoming primary resistance. Our findings establish STING-driven CD200⁺ TAM accumulation and subsequent eosinophil dysfunction as critical determinants of radioresistance, positioning CD200R blockade as a promising therapeutic strategy to potentiate radioimmunotherapy responses in patients with HCC. Graphical abstract of the study findings. Radiotherapy-induced STING signaling activation promotes the accumulation of CD200⁺ TAMs. These CD200⁺ TAMs facilitate the recruitment of eosinophils via the CCL3-CCR1 chemotaxis axis while simultaneously suppressing eosinophil-mediated antitumor activity through CD200-CD200R engagement (left panel). Targeted blockade of CD200R following radiotherapy unleashed the antitumor potential of eosinophils, leading to enhanced infiltration and effector function of CTLs (right panel).

PMID:
42595852
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

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