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

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.