Radiotherapy is a cornerstone of cancer treatment, killing tumor cells either by directly causing DNA double-strand breaks or by indirectly mediating "abscopal effects" through the activation of immune responses [1].

However, radiotherapy can also trigger pro-tumor immune responses that weaken the efficacy of treatments or even lead to their failure, highlighting the "double-edged sword" nature of radiation-induced immunity [2-4].

Researching the immunological mechanisms behind these bidirectional effects and exploring how to scientifically formulate radio-immunotherapy strategies can provide new directions for multidisciplinary comprehensive cancer treatment.

The team led by Han Suxia and Ma Jinlu from the Department of Radiation Oncology at the First Affiliated Hospital of Xi'an Jiaotong University (XJTU), along with the team guided by Hou Yuzhu from the School of Basic Medical Sciences of XJTU, published a research achievement titled CXCR5⁺ monocyte emigration impairs the radiation-induced antitumor immune response in Nature Communications on March 19.

This is the first study to identify the critical role of CXCR5⁺ monocytes in radiation resistance. It clarifies the mechanisms by which CXCR5⁺ monocytes inhibit radiation-mediated antitumor immune responses across several dimensions — production, migration, function, and differentiation — providing a theoretical basis for radio-immunotherapy and a new strategy for comprehensive cancer treatment.

The study found that monocytes enrich in tumor tissues following irradiation, with a significant increase in the CXCR5⁺ subset. In tumor-bearing mice, the number and proportion of CXCR5⁺ monocytes in peripheral blood and bone marrow rose, suggesting such sites act as "reservoirs" for these cells.

Further investigation revealed that tumor-derived VEGF induces CXCR5 expression in bone marrow monocytes by activating the PI3K/Akt/mTOR/HIF1-α pathway. Radiation promotes the production of the chemokine CXCL13 by tumor cells. As the specific ligand for CXCR5, CXCL13 drives the infiltration of CXCR5⁺ monocytes from the reservoirs into the irradiated tumor tissue.

These CXCR5⁺ monocytes highly express PD-L1, which inhibits CD8⁺ T cells via the PD-1/PD-L1 axis, leading to a decrease in the number and function of cytotoxic T lymphocytes (CTLs) and impairing the efficacy of radiotherapy.

At the same time, levels of the GM-CSF protein increase in irradiated tumor tissue, inducing the differentiation of CXCR5⁺ monocytes into CXCR5⁺ M2-like macrophages, which also function to suppress CD8⁺ T cells.

The research team analyzed monocytes in the tumor tissues and peripheral blood of patients before and after radiotherapy. The results showed CXCR5⁺ monocyte infiltration in irradiated tumors, and patients whose cancer progressed after radiotherapy exhibited a significantly higher proportion of peripheral blood monocytes.

By combining radiotherapy with the blockade of the CXCR5-CXCL13 axis, inhibition of PD-1/PD-L1 signaling, and neutralization of GM-CSF, the team enhanced the effectiveness of radiotherapy. Elucidating this mechanism offers a new direction for refining comprehensive treatment strategies and improving prognosis for cancer patients.

References:

1. Wang, L., et al., Radiotherapy and immunology. J Exp Med, 2024. 221(7).

2. Piffko, A., et al., Radiation-induced amphiregulin drives tumour metastasis. Nature, 2025. 643(8072): p. 810-819.

3. Wang, L., et al., YTHDF2 inhibition potentiates radiotherapy antitumor efficacy. Cancer Cell, 2023. 41(7): p. 1294-1308 e8.

4. Hou, Y., et al., Radiotherapy Enhances Metastasis Through Immune Suppression by Inducing PD-L1 and MDSC in Distal Sites. Clin Cancer Res, 2024. 30(9): p. 1945-1958.