Tumor-cell HMGB1 restrains CD8⁺ T-cell immunity during conventional fractionated radiotherapy.

Authors

Chen Chen, Jiahong Shi, Peihai Cao, Juan Bai, Yutiantian Lei, Mengdi Huang, Mingjun Si, Ruiying Wang, Tingting Lv, Rui Jia, Qiuyu Mu, Dingge Jiang, Yuzhu Hou, Shan Huang

Published in

Cancer letters. Pages 218843. Sep 19, 2026. Epub Sep 19, 2026.

Abstract

Conventional fractionated radiotherapy (CFRT) remains a mainstay for many solid tumors, yet it often fails to elicit durable anti-tumor immunity. How CFRT engages tumor-cell programs to shape the immune microenvironment and determine therapeutic outcome remains unclear. Here we show in preclinical mouse models that CFRT is associated with increased tumor-cell HMGB1 relative to stereotactic body radiotherapy (SBRT), and that loss of tumor-cell HMGB1 eliminates the efficacy gap between the regimens. HMGB1 deficiency markedly restrains tumor progression under CFRT in immunocompetent, but not immunodeficient, hosts, accompanied by increased intratumoral CD8⁺ T cells and effector function. In esophageal squamous cell carcinoma (ESCC) specimens from patients receiving CFRT plus platinum-based chemotherapy, tumor-cell HMGB1 increases after treatment, and elevated pretreatment HMGB1 is associated with poor treatment response, reduced post-treatment CD8⁺ T-cell infiltration, and adverse outcomes. Mechanistically, HMGB1 restrains CFRT-induced CD8⁺ T-cell immunity through two convergent arms: CCL2-CCR2-dependent accumulation of suppressive monocytes and FUT8-linked regulation of PD-L1 fucosylation in tumor cells. TCF4 is linked to HMGB1-dependent induction of CCL2 and FUT8. Blocking CCL2 or inhibiting PD-L1 fucosylation restores CD8⁺ T-cell effector function and enhances CFRT efficacy, alone or in combination with anti-PD-1 therapy. Together, these findings identify a tumor-cell HMGB1 program that underpins CFRT-associated immune suppression and nominate actionable targets to improve CFRT-immunotherapy combinations.

PMID:
42762963
Bibliographic data and abstract were imported from PubMed on 20 Sep 2026.

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