Immune checkpoint inhibitors (ICIs) has brought a novel treatment to cancer patients, but they can also lead to adverse reactions, with myocarditis being a common complication [1]. The mortality rate of ICIs-related myocarditis is alarmingly high, nearing 50 %[2]. Current clinical strategies are insufficient in effectively managing this issue, posing a significant obstacle to ICIs treatment. Previous studies have highlighted the infiltration of CD8 + T cells and a small number of macrophages in PD-1-induced lymphocytic myocarditis [3]. However, the precise role of immune cells in ICIs-related myocarditis remains unclear. Further research is needed to elucidate the underlying mechanisms and develop effective interventions for this condition.

Multiple studies have provided evidence that sustained pressure on the heart can lead to fibrosis, thinning of microvessels, and a decline in cardiac function [4]. Additionally, constant pressure stimulates the proliferation of cardiac immune cells, activating and potentially influencing the disease process [5]. Research has shown that CD64 + and F4/80 + macrophages are the main immune cells that accumulate in cardiac tissues after pressure overload, followed by monocytes, dendritic cells, polymorphonuclear leukocytes, and B cells [6]. Macrophages play a crucial role in various diseases and can be classified into different phenotypes, including M1, M2, TAM, and others, depending on the stimuli they receive [7]. Different subtypes of macrophages exert pro-inflammatory or anti-inflammatory effects by secreting distinct cytokines [8]. Consequently, the potential biological functions of macrophages in ICIs-associated myocarditis have piqued the interest of researchers. Further investigations are necessary to fully understand the involvement of macrophages in this condition.

Currently, glucocorticoid shock therapy is the primary treatment for ICIs-related myocarditis in clinical practice [9]. However, high dose of glucocorticoid will lead to a series of adverse reactions such as steroid diabetes [10]. Therefore, finding effective drugs with fewer side effects for ICIs-associated myocarditis remains an unresolved scientific problem. The Janus kinase signal transduction and transcriptional activation (JAK-STAT) signaling pathway has been identified as a target for inflammatory diseases [11]. Clinical evidence suggests that various clinical syndromes are triggered by JAK and STAT mutations [12]. Several drugs targeting JAK have been developed and have shown satisfactory therapeutic effects in clinical research [13], [14]. Thus, exploring whether JAK-targeting drugs can provide therapeutic benefits for ICIs-related myocarditis is the main focus of this study.

Baricitinib, a representative Janus kinase inhibitor, has received approval for the treatment of rheumatoid arthritis, COVID-19, and other inflammatory diseases [15], [16], [17]. Studies conducted on mouse models of systemic lupus erythematosus have shown that baricitinib effectively reduces autoimmune activity by inhibiting abnormal B cell activation and podocellular abnormalities, leading to the alleviation of renal inflammation in lupus-susceptible mice [18]. This suggests that baricitinib, as a selective JAK inhibitor, could serve as a potential treatment option for systemic lupus erythematosus in the future. In rodent models of rheumatoid arthritis, baricitinib has demonstrated a protective effect by inhibiting downstream STAT activation, particularly STAT3, and blocking the intracellular signal transduction of various pro-inflammatory cytokines such as IL-6 and IL-23 [19]. However, the therapeutic effect of baricitinib in ICIs-related myocarditis has not been reported in previous literature. Further research is needed to investigate the potential benefits of baricitinib in this specific condition.

In this study, we nvestigated the effects and underlying mechanism of baricitinib in the context of ICIs-related myocarditis using a mouse model. The results demonstrated that baricitinib exhibited protective effects against ICIs-related myocarditis. This protection was achieved through the promotion of M2-type macrophage polarization, which in turn inhibited the activation of the JAK1-STAT3 signaling pathway. To further validate the protective effects of baricitinib, the researchers employed the Janus kinase agonist RO8191 to counteract the biological effects of baricitinib, confirming its efficacy in mitigating ICIs-related myocarditis. These findings shed light on the potential therapeutic role of baricitinib in the management of ICIs-related myocarditis.