Targeting estrogen receptor potentiates responsiveness to PD-1 blockade by inducing HMGB1 SUMOylation 3304

Description Cold tumors, typically lacking infiltrating lymphocytes, are resistant to immune checkpoint inhibitors (ICIs). Patients with estrogen receptor–positive (ER+) breast cancer (BC), which account for most cases of BC, have fewer TILs and respond more poorly to ICIs than other BC subtypes. However, why ER+ BC immunologically cold remains unclear. Here,we reveal that patients with ER BC tended to achieve higher pCR rates after NAC compared with patients with ER+ BC in our internal cohort and an external cohort. ER−breast cancers elicit an enhanced immune response after chemotherapy by inducing immunogenic cell death (ICD) through high mobility group box 1 (HMGB1) release. Using an immunocompetent ER+ mouse BC model, we demonstrated that combination therapy of fulvestrant, an ER antagonist, and chemotherapy potentiates responsiveness to PD-1blockade via HMGB1. Mechanically, ER directly interacts with HMGB1 and inhibits its SUMOylation and thereby release from the nucleus. Overall, combining ER antagonists and chemotherapy can potentially unleash the clinical benefit of ICIs.