While immunotherapy to target immune checkpoints and modulate immune responses has revolutionized oncology, its applications in CVD are underexplored. Below, we discuss each immunotherapeutic modality and its potential for treating cardiac and cardiovascular conditions.

Antibodies, cytokines, and immunotherapy. A promising avenue for application of immunotherapy to CVD is modulating T cell effector responses and promoting Treg activity (93, 94). Intravenous administration of anti-CD3–specific antibodies effectively suppresses effector T cell immune responses and reduces atherosclerosis in mice by inducing TGF-β–producing CD4+CD25+ LAP+ Tregs, which in turn inhibit experimental autoimmunity in a TGF-β–dependent manner (95, 96). Combining anti-CD3 antibodies with IL-2 complexes increases Treg numbers and halts the progression of atherosclerosis in ApoE–/– mice (97). On the other hand, CD147 inhibition blocks T cell activation and immune cell recruitment to the heart in CVB3-induced myocarditis (98).

Cytokine-based immunotherapies can modulate immune responses, aiding in cardiac repair for patients with HF (99). IL-37, a potent antiinflammatory cytokine that belongs to the IL-1 family, has shown promise for treatment of CVD (100–104). A recent study revealed that IL-37 levels were lower in patients with coronary artery disease (CAD) than in healthy volunteers. Also, IL-37 inversely correlated with inflammatory markers, thus becoming a predictor of CAD, which suggests that its decreased levels in CAD patients are linked to inflammation and disease progression (105). Another clinical study revealed that IL-37 is elevated in patients with acute coronary syndrome, having a beneficial role (106). Recombinant IL-37 administration increases the release of the antiinflammatory cytokines IL-10 and TGF-β from Tregs in vitro. These findings suggest that recombinant IL-37 could mediate antiinflammatory effects in atherosclerosis by enhancing Treg function and cytokine secretion (107).

The CANTOS, LoDoCo, and COLCOT trials have confirmed that targeting inflammation can improve cardiovascular outcome in atherosclerosis (108–110). These studies demonstrated that inhibiting IL-1β and neutrophil function with colchicine reduces the progression of atherosclerotic CVD. Given the important role of adaptive immunity, particularly T cell activation, in atherosclerosis, immune checkpoint inhibitors may also offer important therapeutic benefits for managing the disease.

Th1 cells are the main CD4+ T cells contributing to atherogenesis through their production of IFN-γ and TNF-α. IFN-γ enhances recruitment of macrophages and T cells; promotes macrophage polarization, cytokine secretion, and foam cell formation; and inhibits vascular smooth muscle cell proliferation, leading to decreased plaque stability (111, 112). TNF-α contributes to atherosclerosis by recruiting leukocytes, producing inflammatory cytokines, and causing endothelial damage and oxidative stress (113, 114). Inhibition of Th1 differentiation in mice was shown to have atheroprotective effects by reducing IFN-γ levels in plaques (115).

Treg deficiency is associated with larger and more-advanced atherosclerotic plaques. Treg transfer into Treg-deficient models reduces inflammatory cell infiltration and decreases plaque size (116). In human carotid arteries, a higher number of Tregs inversely correlated with plaque vulnerability, suggesting their importance in maintaining plaque stability (117). This is likely related to their ability to secrete TGF-β and IL-10. In this regard, TGF-β inhibits recruitment and activation of T cells and macrophages while promoting vascular smooth muscle cell proliferation, thereby increasing plaque stability (118). IL-10 reduces IFN-γ expression by T cells, preventing T cell and macrophage recruitment and cytokine secretion (119).

The role of Th17 cells in atherosclerosis is still hotly contested (120, 121). IL-17 and IFN-γ jointly boost inflammation in atherosclerotic plaques (122). However, some studies indicated that IL-17 promotes atherosclerosis (123), while others suggest it enhances plaque stability (124, 125). Moreover, an increased Th17 cell/Treg ratio is found in patients with coronary atherosclerosis. Deletion of the leukocyte receptor CD69, which regulates Th17 cell/Treg differentiation, increases the Th17 cell/Treg ratio and exacerbates atherosclerosis in mice. Additionally, expression of CD69 mRNA in peripheral blood leukocytes from a cohort of participants with subclinical atherosclerosis correlates with a slower progression of atherosclerosis (70). This Th17 cell/Treg balance is crucial in autoimmune conditions and in mitigating adverse effects of immune checkpoint inhibitor therapy, such as myocarditis (126).

T cell adoptive transfer. By modulating the immune response, T cells mitigate inflammation and promote tissue repair in cardiac diseases. Therapeutic approaches that enhance Treg function or increase their numbers are being explored to reduce cardiac inflammation and fibrosis, thereby improving heart function (93, 127). Additionally, targeting specific T cell subsets — such as cytotoxic CD8+ T cells, which are implicated in myocarditis and autoimmune cardiac damage — offers another possible therapeutic avenue. Adoptive T cell transfer, in which patients receive their own modified T cells, and checkpoint inhibitors that regulate T cell activity are also being considered to treat arrhythmias and prevent heart tissue damage after an MI. These strategies highlight the potential of T cell–based therapies to provide targeted and effective treatments for a range of CVDs.

Cardioprotective Tregs, particularly CD4+ T cells reacting with α-MyHC, accumulate in the injured myocardium in humans and mice, becoming beneficial when delivered before MI in mice (78, 128). Foxp3+ Tregs also improve heart outcomes in mice and rats, through either autologous Treg infusion or CD28 antibody administration, which enhances Treg recruitment (129, 130). Boosting Treg accumulation in the injured heart is another promising therapeutic approach to treat human HF (131). Adoptive transfer of Tregs protected against CVB3-induced myocarditis by different mechanisms, including suppression of the immune response, fibrosis, reduction of virus titers, and improvement of cell survival via increased phosphorylation of AKT (132, 133). Adoptive transfer of Tregs inhibits the proinflammatory microenvironment of the plaque and controls the development of atherosclerosis (116). In a clinical setting, Tregs alleviate allograft rejection, but adult-derived Tregs have limitations. To overcome this, a new method uses high-quality Tregs from thymic tissue removed during pediatric cardiac surgeries (thyTregs). A phase I/II clinical trial with a 2-year follow-up of the first treated patient showed no adverse effects and conserved Treg frequency. These results support the safety and potential of autologous thyTreg therapy to restore the Treg pool in infants undergoing heart transplantation (134).

Immune checkpoints. A promising therapeutic avenue is targeting immune checkpoints and modulating immune responses. While immunotherapy has revolutionized oncology, its applications in CVD are underexplored (135). The CD80/86-CD28 and CD80/86–CTLA-4 immune checkpoints regulate plaque inflammation in atherosclerosis (136). CD80/86+ macrophages and CD28+ T cells are more prevalent in vulnerable plaques than in stable ones. Mice deficient in CD80 and CD86 display reduced atherosclerosis and lower IFN-γ production by effector T cells, indicating that CD28-CD80/86 interactions prime T cells in atherosclerosis (137). Mice overexpressing CTLA-4 have defective effector T cell responses and developed less atherosclerosis (138). Pharmacological inhibition of CD28-CD80/CD86 with the CTLA-4–Ig fusion protein abatacept reduced atherosclerosis in mice (139). The CD40L-CD40 interaction is a crucial immune-checkpoint target in CVD, enhancing T cell stimulation and macrophage, DC, and B cell activation. It is also essential for B cell Ig-isotype switching in germinal centers. In ApoE–/– and LDLR–/– mice, genetic deletion or antibody-mediated inhibition of CD40L or CD40 reduced atherosclerotic plaque burden and induced stable, collagen-rich plaques (140–142). In humans, CD40L-CD40 expression in plaques is linked to plaque vulnerability. The soluble form, sCD40L, is associated with hypercholesterolemia, stroke, diabetes, and acute coronary syndrome and can accurately predict recurrent CVD (143).

CAR T cells. Chimeric antigen receptors (CARs) are synthetic receptors composed of four main components: an extracellular antigen-binding domain, a hinge region, a transmembrane domain, and intracellular signaling domains. CAR T cell therapy has generated significant excitement for its ability to eradicate advanced leukemias and lymphomas, like immune checkpoint inhibitors. The use of CAR T cell therapies in CVDs is being explored, with promising preliminary results (144–146). Early studies suggest that CAR T cell–based therapies could potentially be adapted to target specific cardiovascular conditions. A therapeutic approach has been developed using modified mRNA in lipid nanoparticles (LNPs) to create transient antifibrotic CAR T cells in vivo. In a mouse model of HF, CD5-targeted LNPs efficiently delivered CAR-encoding mRNA to T cells, generating effective CAR T cells that reduced fibrosis and restored cardiac function (147). These initial findings open new avenues for treatment, offering hope for effective management and improved outcomes in patients with cardiovascular disease.