Abstract

Background Immunotherapy has revolutionized the treatment of malignant tumors; however, it may lead to fatal cardiotoxicity. Herein, we explored the mechanisms underlying cardiac side-effects induced by immune checkpoint inhibitors (ICIs) and proposed a promising therapeutic target. Methods Serum samples were collected from 168 patients with advanced non-small cell lung cancer (NSCLC) receiving ICIs treatment or not. Representative ICI (IBI308) was intraperitoneally injected into normal C57BL/6 and congenital immune deficient nude mice. NOD-like receptor family, pyrin domain containing 3 ( Nlrp3 ) globally knockout mice and gasdermin D ( Gsdmd ) globally knockout mice were involved in this study. Mice with cardiac-specific BTB domain and CNC homolog 2 (Bach2) knock-in and knock-out were also included. The Cleavage Under Targets and Tagmentation (CUT&Tag) experiment was conducted to identify downstream molecules of BACH2, which was further validated with dual-luciferase and electrophoretic mobility shift assays (EMSA). A library of small-molecule products was screened to identify a specific agonist of BACH2, followed by in vivo and in vitro verification. Results Patients treated with ICIs had significantly higher cardiac troponin T (cTNT) and interleukin 18 (IL-18) levels. IBI308 significantly reduced cardiac function, increased cardiac fibrosis, and induced myocyte pyroptosis in wild type mice and T-cell deficient nude mice. IBI308-elicited toxicity was reversed by depleting pyroptotic genes Nlrp3 or Gsdmd . Furthermore, cardiac-specific knock-in of Bach2 rescued, whereas cardiac-specific knock-out of Bach2 exacerbated IBI308-induced cardiotoxicity and pyroptosis. BACH2 directly bound to the promoter of G-Rich RNA sequence binding factor 1 ( GRSF1 ) and promoted its transcription, which then activated the nuclear factor κB (NF-κB) signaling cascade. The protective eff