Immune Cell-Mediated Inflammation in Heart Failure: Subset Heterogeneity and Targeted Therapy

Abstract

Heart failure (HF) is the end-stage manifestation of various cardiovascular diseases, affecting over 64 million patients globally. Current standard therapies have substantially improved the prognosis of patients with HF with reduced ejection fraction (HFrEF), but show limited efficacy in HF with preserved ejection fraction (HFpEF), and the overall cure rate remains unsatisfactory. Persistent low-grade sterile inflammation mediated by immune cells is a core pathological driver of HF onset and progression. The high complexity of the cardiac immune microenvironment, along with the phenotypic and functional heterogeneity of immune cells, has made targeted immunotherapy a key research focus in this field. This review focuses on the core perspective of immune cell subpopulation heterogeneity, systematically summarizing the functional characteristics, cell interaction networks, and targeted treatment progress of key immune cells in HF. The aim is to provide comprehensive academic references for basic research and clinical translation in this field. Based on relevant literature published in PubMed from 2021 to 2026, this review systematically summarizes the heterogeneity characteristics and functional transition patterns of macrophages, T cells, neutrophils, and dendritic cells in HF. It dissects the local interaction network between immune cells and resident cardiac cells (including cardiomyocytes and fibroblasts), as well as the cross-organ regulatory mechanism of the immune-adipose-heart axis. Meanwhile, the latest research progress in small-molecule drugs, biological agents, and novel therapeutic strategies targeting immune cells is comprehensively summarized. Finally, this review identifies gaps in current research regarding the spatiotemporal dynamic evolution of immune cells, clinical translation, therapeutic precision and safety, and cross-system regulatory mechanisms, and outlines future directions including high-resolution spatiotemporal immune atlas construction, precise targeting technology development, and individualized immune diagnosis and treatment.

Introduction

Heart failure (HF) is the end stage of various cardiovascular diseases, characterized by high incidence, high readmission rate, and high mortality. According to the latest Global Burden of Disease data, more than 64 million people worldwide are living with HF.¹ Over the past decades, the new quadruple therapy—represented by angiotensin receptor-neprilysin inhibitors (ARNIs), β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2is)—has greatly improved the prognosis of patients with HFrEF.² However, overall prognosis remains poor; in particular, there is still a lack of effective interventions for HFpEF, leaving substantial unmet clinical needs.

Classification of HF

The clinical classification of HF is primarily based on left ventricular ejection fraction (LVEF). The 2021 ESC guidelines classify HF into HFrEF (LVEF ≤ 40%), heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41–49%), and HFpEF (LVEF ≥ 50%), among which HFmrEF was previously referred to as “heart failure with mid-range ejection fraction”.³ The AHA/ACC/HFSA guidelines further define heart failure with improved ejection fraction (HFimpEF) as patients whose LVEF increases from ≤ 40% to > 40% after treatment.⁴ In primary care populations, HFrEF is the most common phenotype (approximately 43%), followed by recovered HFrEF (31%) and HFpEF (26%).⁴ However, the classification system relying solely on LVEF has significant limitations. Etiological classification and more modern classification frameworks deserve greater attention, as different LVEF phenotypes present essential differences in pathophysiological mechanisms, metabolic characteristics, and treatment responses.⁵

Classic Pathogenetic Mechanisms of HF

Five major categories of classic HF pathogenetic mechanisms are widely recognized. The understanding of HF pathophysiology has evolved from pure hemodynamic disturbance to a clinical syndrome driven by both neuroendocrine and proinflammatory factors, and further expanded to multi-organ dysfunction and energy metabolism disorders.

Excessive neuroendocrine activation is one of the core mechanisms. Cardiac injury reduces cardiac output and activates the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS). While compensatory in the short term, sustained long-term activation exerts detrimental hemodynamic and direct cardiovascular effects, and this phenomenon is also observed in HFpEF.⁶

Cardiomyocyte injury and death form the cellular basis of HF. Cardiomyocytes undergo progressive loss via multiple regulated cell death pathways, including apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Mitochondrial dysfunction exacerbates this process through calcium dysregulation, oxidative stress, and proteotoxic injury.⁷

Myocardial fibrotic remodeling, characterized by excessive collagen deposition, distorts normal cardiac structure and impairs interstitial biological function. It is a shared pathological feature across all HF phenotypes, yet no effective targeted intervention is currently available.

Microvascular endothelial dysfunction plays a particularly critical role in HFpEF. Coronary microvascular dysfunction (CMD) is involved in HFpEF progression; patients exhibit reduced cardiac microvascular density, systemic endothelial dysfunction, and impaired coronary flow reserve, and endothelial cells mediate the association between CMD and HFpEF.⁸

Myocardial energy metabolism disorder is a non-negligible component of HF. The failing heart faces energy insufficiency, mainly caused by decreased mitochondrial oxidative capacity, leading to a mismatch between ATP production and demand.⁹

Most classic mechanisms focus on pathological changes in the myocardium itself and only explain part of the HF course. Treatments based on these mechanisms still have intervention gaps, suggesting that incompletely elucidated pathological pathways contribute to HF progression.

Inflammatory and Immune Heterogeneity Across HF Phenotypes

Accumulating evidence indicates that distinct inflammatory activation patterns and immune cell lineages underlie different HF phenotypes. Although HFrEF and HFpEF share some risk factors and adverse cardiac remodeling features,¹⁰ their immunological mechanisms are fundamentally different. Single-cell sequencing studies have confirmed that peripheral blood monocytes from HFpEF patients have unique transcriptional immune signatures, distinct from those of HFrEF patients: inflammation in HFrEF is mainly monocyte-driven, whereas HFpEF exhibits a natural killer (NK) cell-driven inflammatory signature.¹¹ However, other studies note that low-grade systemic inflammation exists in the hearts of both HFpEF and HFrEF patients, and no specific HFpEF inflammatory phenotype has been identified to date.

Ten immune cell types are significantly altered in ischemic cardiomyopathy (ICM) cardiac tissue, among which CD56^dim NK cells show extensive and significant correlations with other immune cells.¹² T cells play a key role in hypertension and HF: multiple stimuli induce effector T cell formation and infiltration of the cardiovascular wall.¹³ In cardiometabolic HFpEF (cmHFpEF), metabolic stress, hemodynamic stress, immune activation, and systemic inflammation collectively drive disease progression.

Challenges in HF Immunotherapy

Current HF immunotherapies face numerous challenges. Early regimens such as broad-spectrum anti-inflammatory therapy and anti-TNF-α therapy all ended in clinical failure. The core reasons include the high redundancy of immune pathways, compensatory activation effects, and disease heterogeneity; non-specific interventions tend to disrupt physiological immune defense functions.

Existing reviews mostly focus on a single immune cell type or therapeutic direction, lacking a holistic integration of subset function, local cell communication, cross-organ regulation, and targeted therapy systems from the perspective of immune cell heterogeneity. Furthermore, updates on new immune subset insights revealed by single-cell technologies in recent years are insufficient. Therefore, systematic investigation of the mechanisms of different immune cell subsets in HF and their functional transitions in specific spatiotemporal contexts, as well as the interaction network between immune cells and the myocardial microenvironment, is of great theoretical and clinical value for developing safer and more effective HF immunotherapeutic strategies. This study hypothesizes that the phenotypic heterogeneity and dynamic functional transition of different immune cell subsets are core determinants of HF inflammatory outcomes, and precise targeting of specific pathogenic immune subsets can effectively inhibit adverse myocardial remodeling while preserving physiological immune defense.

Accordingly, using heart failure, immune cell, inflammation, macrophage, T lymphocyte, neutrophil, dendritic cell as core search terms, we retrieved PubMed literature published from January 2021 to June 2026, including original basic research, clinical trials, systematic reviews, and high-quality narrative reviews, with supplementary inclusion of classic high-impact literature in the field. Centered on immune cell subset heterogeneity, this review systematically sorts out the phenotypic characteristics and functional transition patterns of major immune cells in HF, and elaborates on the interaction network between immune cells and resident cardiac cells. It also summarizes the latest progress in HF therapeutic strategies targeting immune cells, aiming to provide a comprehensive reference for basic research and clinical translation in the field. No meta-analysis was conducted in this study, and no pooled statistical assessment was performed. All conclusions are based on the qualitative review of published literature.

Heterogeneity Characteristics of Major Immune Cell Subsets in HF

Heterogeneity and Functional Transition of Macrophages

Origin and Subset Classification of Cardiac Macrophages

Cardiac macrophages include embryo-derived resident macrophages and bone marrow-derived monocyte-derived macrophages.¹⁴ Tissue macrophage heterogeneity follows a hierarchical origin: during embryonic development, myeloid progenitors from the yolk sac and fetal liver gradually colonize and differentiate into tissue-resident macrophages. After birth, circulating bone marrow-derived monocytes differentiate into infiltrating macrophages under induction by tissue microenvironmental signals. Cell origin, microenvironmental signals, and pathological stimulus types collectively determine macrophage phenotypic and functional heterogeneity, resulting in functional differences across tissues and across subsets within the same tissue.¹⁵

Single-cell studies of human macrophage development have further confirmed a clear hierarchical differentiation path, from hematopoietic stem and progenitor cells through myeloid progenitors to monocyte precursors. Different tissue microenvironments shape tissue-specific macrophage characteristics via transcriptional regulatory networks, providing a developmental biological basis for dissecting cardiac macrophage subset heterogeneity.¹⁶

Single-cell transcriptomics has revealed that cardiac macrophages exhibit high heterogeneity in both homeostatic and diseased states.¹⁷ In HF, CCR2⁺ macrophages expand significantly as the main pathogenic subset, while resident CCR2⁻ macrophages gradually decrease, suggesting that macrophage subset imbalance may be an early driver of HFpEF onset.¹⁸ Studies have shown that bone marrow-derived macrophages are the main population driving adverse remodeling in chronic ischemic HF,¹⁹ while loss of embryo-derived macrophage function is key to HF progression in pressure-overload HF.²⁰

Regulatory Mechanisms of Macrophage Polarization

Macrophage polarization is the core of functional transition, traditionally divided into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. M1 macrophages are activated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ), secrete high levels of pro-inflammatory factors (IL-1β, TNF-α, IL-6), and activate the NF-κB and NLRP3 inflammasome pathways.²¹ M2 macrophages are polarized by IL-4 and IL-13, express high levels of CD206 and CD163, and secrete anti-inflammatory factors and repair mediators.²² However, recent studies have found that macrophages in the HF microenvironment do not follow a simple M1/M2 binary pattern, but exist as multiple functional subsets requiring classification at the single-cell level.²³

Wang et al identified a special M2 subset — CD206⁺IL-4Rα⁺ macrophages — as a key driver of adverse remodeling in ischemic cardiomyopathy. After myocardial infarction, this subset accounts for 85% of total cardiac macrophages. It activates the Notch signaling pathway via high FIZZ1 expression, inducing the differentiation of cardiac mesenchymal stem cells and fibroblasts into myofibroblasts. In vivo silencing of IL-4Rα specifically depletes this subset, reverses ventricular remodeling, and improves angiogenesis.¹⁹

Notably, there is significant controversy regarding the role of IL-4Rα signaling in HF. Parthiban et al found that IL-4Rα activation stimulates cardiac fibroblast fibrosis in mice,²⁴ while Alvarez-Argote et al showed that global IL-4Rα blockade exacerbates post-infarction HF in both mice and humans.²⁵ The core discrepancy likely stems from differences in disease stage and experimental model: the former focuses on the chronic myocardial fibrosis stage, while the latter targets the acute repair phase of myocardial infarction. IL-4Rα-mediated M2 polarization clears necrotic tissue and promotes angiogenesis during acute injury, but continuously drives excessive fibroblast activation in the chronic phase. This controversy confirms that macrophage function in HF is not binary, and its effects are highly dependent on disease context and microenvironmental state.

Significance of Macrophage Efferocytosis

Efferocytosis is a key process for clearing apoptotic cells and maintaining tissue homeostasis.²⁶ Recent studies have confirmed that macrophage-mediated efferocytosis not only blocks sterile inflammation initiation and amplification by clearing apoptotic cells and reducing damage-associated molecular pattern (DAMP) release, but also promotes anti-inflammatory polarization via post-phagocytic reprogramming, secretes repair cytokines and growth factors, and accelerates inflammation resolution and wound healing. Defective efferocytosis leads to secondary apoptotic cell necrosis and persistent inflammation, which is a core driver of chronic inflammatory disease progression.²⁷

In cardiac injury and HF progression, abnormal macrophage efferocytosis impairs clearance of apoptotic cardiomyocytes and interstitial cells. Sustained DAMP release further activates innate immune inflammatory pathways, exacerbating myocardial injury and fibrotic remodeling. Therefore, restoring macrophage efferocytosis has become a potential direction for anti-inflammatory and reparative HF therapy. Studies have found that CD300a deficiency enhances resident macrophage efferocytosis and reduces DAMP release, thereby attenuating cardiac injury and adverse remodeling after ischemia-reperfusion.²⁸ MerTK-mediated clearance of apoptotic myocytes accelerates inflammation resolution and increases vascular endothelial growth factor A (VEGFA) secretion, promoting cardiac repair after injury.²⁹

Heterogeneity and Immune Regulation of T Cell Subsets

Imbalanced T cell quantity and abnormal function are important mechanisms for persistent chronic inflammation in HF. Different T cell subsets exert opposite regulatory effects on cardiac repair and pathological injury.

Dual Regulation and Phenotypic Plasticity of Regulatory T Cells

Regulatory T cells (Tregs) are the body’s core immunosuppressive cells, with dual anti-inflammatory and tissue repair functions in HF. Tregs in the heart and aortic tissue have unique transcriptional phenotypes and tissue-specific heterogeneity: they inhibit excessive inflammation via anti-inflammatory factor secretion, while promoting myocardial angiogenesis, regulating fibroblast activation, and maintaining myocardial microenvironment homeostasis.^30,31 In hypertensive HF, Treg numbers decrease and function is exhausted, failing to suppress pro-inflammatory activation of myeloid and effector T cells, leading to amplified inflammation.³¹

However, Treg function in HF is not uniform. Sustained inflammatory signals induce Treg phenotypic reprogramming, loss of Foxp3 expression, and even transformation into pathogenic Th17-like ex-Tregs, indicating that their effects are modulated by disease stage and the local microenvironment.³² Most current Treg studies rely on adoptive transfer in animal models; the difficulty of in vivo Treg regulation limits the safety and stability of clinical translation.

Dual Role of CD8⁺ T Cells and Direct Myocardial Injury

As core adaptive immune effector cells, CD8⁺ T cells exhibit high subset heterogeneity, including naive, effector, memory, and exhausted subsets. These subsets differ significantly in cytokine secretion, cytotoxicity, and immune regulation, playing distinct roles in immune defense, tissue injury, and immune modulation in inflammatory diseases.³³

In viral myocarditis-induced HF, CD8⁺ T cells initially clear infected cardiomyocytes to limit viral replication.³⁴ In non-infectious HF, however, CD8⁺ T cells recognize MHC class I complexes on cardiomyocyte surfaces and directly induce apoptosis via perforin and granzyme B release.^35,36 In a left ventricular dysfunction model, abnormal CD8⁺ T cell activation induces pulmonary inflammation, vascular remodeling, and right ventricular hypertrophy; specific CD8⁺ T cell depletion significantly reverses these pathological changes. Treg deficiency further exacerbates CD8⁺ T cell activation and tissue infiltration, accelerating HF progression.³⁷ These findings confirm that CD8⁺ T cell function is also highly context-dependent.

Heterogeneity and Inflammatory Effects of Neutrophils

As the first innate immune cells to respond to tissue injury, neutrophils play a bidirectional regulatory role in both acute injury and chronic HF courses. Their subset heterogeneity, chemotactic infiltration, and neutrophil extracellular trap (NET) formation are key regulators of HF inflammation and remodeling.

Neutrophil heterogeneity underlies their dual functions. Based on phenotype and function, they are divided into pro-inflammatory and reparative subsets: pro-inflammatory neutrophils highly express chemokine receptors and degranulation-related molecules, amplifying inflammation and mediating tissue damage via proteases, reactive oxygen species, and NETs; reparative neutrophils highly express anti-inflammatory and repair-related molecules, participating in apoptotic cell clearance, angiogenesis, and tissue remodeling. The dynamic balance between the two determines inflammatory disease outcomes.³⁸

In early acute myocardial injury, rapid neutrophil infiltration is necessary to initiate inflammation and clear necrotic debris, and only causes damage when continuously overactivated. In chronic HF, long-term abnormal neutrophil activation and systemic inflammatory positive feedback drive disease progression. In chronic HF, neutrophils not only increase in number, but also undergo significant transcriptomic and functional changes. Under physiological conditions, neutrophils participate in debris clearance and repair initiation;³⁹ when continuously overactivated, they release proteases and inflammatory factors, form NETs, and induce microvascular thrombosis, myocardial inflammation, and interstitial fibrosis, driving HF progression.^40,41

During chronic HF, bone marrow granulopoiesis is enhanced, and neutrophils continuously infiltrate the peripheral blood and cardiac border zone. High expression of CXCL1 and CXCL5 further recruits circulating neutrophils, forming a positive inflammatory feedback loop.⁴⁰ The CD300a immune receptor negatively regulates neutrophil activation in the HF microenvironment. SiglecF^hi neutrophils infiltrate abundantly in ischemia-reperfusion cardiac injury and amplify the inflammatory cascade; reducing this subset alleviates ischemic myocardial injury.²⁸

NETosis is a unique programmed death mode of neutrophils,⁴² mediated by MPO, NE, and PAD4. It releases DNA reticular structures wrapped with inflammatory proteases, playing a core pathogenic role in sterile cardiac inflammation.⁴³ In HFpEF, massive NET deposition induces myocardial microvascular thrombosis, hypoxia, and cell death. KLF2 is a key transcription factor regulating neutrophil activation and NETosis. KLF2 expression is significantly downregulated in neutrophils from HF patients and model animals, and it activates the NETosis pathway via crosstalk with HIF-1 signaling, driving myocardial hypertrophy and cardiac function decline.⁴⁴ The HMGB1-TLR4 axis is recognized as a key upstream signal for NET formation.⁴⁵

Antigen-Presenting Function of Dendritic Cells

Dendritic cells (DCs) have multiple origins and subsets. Derived mainly from bone marrow hematopoietic stem cells, they are divided into two lineages: myeloid-derived conventional DCs (cDCs) and plasmacytoid DCs (pDCs), differentiated from common myeloid progenitors and common lymphoid progenitors, respectively. cDCs are further divided into cDC1 and cDC2 subsets, which play distinct roles in antigen presentation and T cell differentiation. Their development is precisely regulated by cytokines (FLT3L, GM-CSF) and transcription factors; phenotypic and functional heterogeneity determines their bidirectional roles in immune activation and tolerance.⁴⁶

As the body’s most potent antigen-presenting cells, DCs bridge innate and adaptive immunity⁴⁷ and play a key regulatory role in HF inflammatory imbalance. Resident cDCs in healthy hearts usually exhibit a tolerogenic phenotype, maintaining peripheral immune tolerance by taking up small amounts of dead cardiomyocyte antigens and presenting them to T cells.⁴⁸

After myocardial infarction, DCs highly express TSLP receptors. TSLP modulates DC function to further regulate CD4⁺ T cell (especially Treg) activation and proliferation. TSLP receptor deficiency reduces post-infarction Treg numbers and causes excessive myeloid cell infiltration, exacerbating myocardial fibrosis and cardiac dysfunction.⁴⁹ DCs also activate CD8⁺ T cells and Th1 cells via antigen presentation,⁵⁰ amplifying local cardiac inflammation and contributing to pressure-overload HF progression. Fibrosis-targeted engineered immunosuppressive DCs reduce inflammatory myocardial fibrosis, improve cardiac perfusion, and preserve contractility, effectively preventing pathological cardiac remodeling.⁵¹

Table 1 summarized the major immune cell subsets in HF, as well as their characteristic molecular markers and core biological functions.

Table 1.

Origin, Markers, and Core Biological Functions of Key Immune Cell Subsets in Heart Failure

Immune Cell Subset	Characteristic Molecular Markers	Core Biological Functions	References
Macrophages	CCR2⁺	Significantly expanded in HF as the major pathogenic subset; drives adverse ventricular remodeling	[18]
Macrophages	CD206⁺IL-4Rα⁺	Key driver of adverse remodeling in ischemic cardiomyopathy; activates Notch signaling via high FIZZ1 expression to induce differentiation of cardiac mesenchymal stem cells and fibroblasts into myofibroblasts	[19]
Regulatory T cells (Tregs)	–	Dual anti-inflammatory and tissue repair functions; secrete anti-inflammatory factors to inhibit excessive inflammation, promote myocardial angiogenesis, regulate fibroblast activation, and maintain myocardial microenvironment homeostasis	[30,31]
CD8⁺ T cells	–	Recognize MHC class I complexes on cardiomyocyte surfaces and directly induce apoptosis via perforin, granzyme B, or the Fas/FasL pathway	[35,36]
Neutrophils	SiglecFhi	Abundantly infiltrate in ischemia-reperfusion cardiac injury and amplify the inflammatory cascade; their reduction alleviates ischemic myocardial injury	[28]
Neutrophils (NETosis)	NETs mediated by MPO, NE, PAD4	Release DNA reticular structures wrapped with inflammatory proteases, playing a core pathogenic role in sterile cardiac inflammation	[44]
Conventional dendritic cells (cDCs)	–	Take up dead cardiomyocyte antigens and present them to T cells to maintain peripheral immune tolerance; regulate CD4⁺ T cell activation and proliferation via the TSLP receptor	[49]

Local Cell Communication and Cross-Organ Regulation Mediated by Immune Cells in HF

HF onset and progression are not simply caused by hemodynamic abnormalities; persistent low-grade inflammation driven by immune cells plays a critical role in myocardial remodeling. In recent years, single-cell sequencing, spatial transcriptomics, and lineage tracing have revealed the complexity and dynamic changes of the cardiac immune microenvironment. A scientific statement from the ESC Heart Failure Association clearly identifies crosstalk between immune activation and metabolic reprogramming as a core pathological feature of HF progression: immune activation triggers metabolic reprogramming to meet the energy demands of effector functions, while metabolic disorders further amplify inflammatory responses, forming a positive feedback loop. Meanwhile, immune cells mediate multi-organ interactions via cytokines and metabolic intermediates, serving as a core link between dysfunction of the heart, adipose tissue, kidneys, and other organs. This cross-system regulatory model also provides a theoretical basis for multi-target HF intervention.⁵²

To visually integrate immune cell subset heterogeneity, cardiac cell crosstalk, immune-adipose inflammatory pathways, and targeted therapeutic targets discussed in this review, we generated a panoramic mechanistic diagram of immune inflammation in HF (Figure 1), which is dissected in detail in the following sections.

Figure 1.

Schematic diagram of immune cell-mediated sterile inflammation in heart failure (HF). Centered on immune cell subset heterogeneity, this figure shows the complete pathological cascade of HF. Left: upstream injury triggers and cross-organ regulatory axes (adipose hyperlipolysis, intestinal flora dysbiosis). Center: phenotypic and functional heterogeneity of core immune cells (macrophages, T cells, neutrophils, dendritic cells), as well as their crosstalk with cardiac resident cells. Right: downstream pathological alterations including myocardial cell death, fibrosis, microvascular dysfunction and energy metabolism disorder, which ultimately progress to HF.

Interaction Network Between Immune Cells and Resident Cardiac Cells

During HF progression, immune cells do not act in isolation, but drive myocardial inflammation, fibrosis, cell death, and dysfunction via a complex bidirectional communication network with resident cells (cardiomyocytes, fibroblasts, endothelial cells).

Immune cell-fibroblast crosstalk is the core pathway of HF fibrosis. Studies have shown that monocytes/macrophages are the main immune cell type regulating cardiac fibroblast activation and fibrosis.⁵³ Amrute et al performed multi-omics analysis on hearts from 45 healthy donors, acute myocardial infarction patients, and chronic HF patients, and revealed for the first time that CCR2⁺ macrophages secrete IL-1β to drive FAP/POSTN⁺ stromal fibroblast differentiation and exacerbate myocardial fibrosis.⁵⁴ Similarly, Parthiban et al identified a cardiac resident macrophage subset with high CCL24 expression, which promotes fibroblast proliferation and activation via the fibroblast CCR3 receptor;²⁴ CXCR4⁺ macrophages secrete CXCL3 to induce myofibroblast differentiation, aggravating diastolic dysfunction in hypertension-induced HFpEF.⁵⁵

Immune cells also directly affect cardiomyocyte function via paracrine signaling. Qian et al found that in an isoproterenol (ISO)-induced HF model, both macrophages and cardiomyocytes activate MD2 protein via β2-AR and β1-AR, respectively. MD2 activation further amplifies inflammation and promotes cardiomyocyte hypertrophy and injury; MD2 inhibition blocks this inflammatory crosstalk and attenuates cardiac remodeling.⁵⁶

Cross-Organ Interaction of the Immune-Adipose-Heart Axis

HF is accompanied by systemic multi-tissue inflammatory linkage, and immune cells mediate cross-regulation between the heart and adipose tissue. Cardiomyocyte-specific p38 MAPKα deletion leads to excessive adipose lipolysis, inducing myocardial lipid deposition and metabolic dysfunction, and simultaneously promoting massive infiltration of neutrophils, macrophages, and lymphocytes into the heart. Adipose lipolysis has been identified as a key driver of increased cardiac inflammation, abnormal myocardial lipid accumulation, and left ventricular dilation.⁵⁷ Inhibiting adipose lipolysis significantly reduces neutrophil infiltration and improves cardiac function.⁵⁸

Under obese conditions, fatty acid metabolism remodeling modulates macrophage phenotypes: n-6 fatty acids impair inflammation resolution, while the n-3 fatty acid DHA promotes expansion of reparative macrophages and Tregs, optimizes the cardiorenal inflammatory microenvironment, and improves post-infarction HF prognosis.⁵⁹

Inflammatory Mechanisms of COVID-19 and Long COVID-Related HF

SARS-CoV-2 infection and long COVID syndrome are important clinical evidence for the role of inflammation in HF progression. Recent studies have confirmed that COVID-19 not only aggravates hemodynamic damage in patients with pre-existing HF, but also significantly increases the risk of new-onset left ventricular dysfunction in the general population. The core pathological mechanism is virus-induced endothelial dysfunction and systemic low-grade inflammation.

SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor on endothelial cells and cardiomyocytes, promoting endothelial dysfunction, inflammation, and hypercoagulability. In endothelial cells, this dysregulation activates a pro-inflammatory state and impairs vascular integrity; in cardiomyocytes, SARS-CoV-2-induced Ca²⁺ imbalance contributes to arrhythmia and HF via abnormal Ca²⁺ cycling and energy metabolism disorders.⁶⁰

Even in the long COVID stage, some patients present with subclinical cardiac dysfunction, including elevated myocardial injury markers and impaired diastolic function.⁶¹ Sustained immune activation and endothelial inflammation slowly drive ventricular remodeling, and long-term increase HF risk via pathways such as myocardial fibrosis, microvascular injury, and abnormal cardiomyocyte metabolism.⁶² This clinical phenomenon further verifies that persistent inflammation is a core driver of HF progression, and provides real-world evidence for clinical anti-inflammatory therapy.⁶³

Therapeutic Strategies Targeting Immune Cells

HF Immunotherapy: Paradigm Shift from Broad-Spectrum Inhibition to Precise Targeting

Given the critical role of immune cells in HF, targeted therapeutic strategies have become a research hotspot. However, the clinical translation of HF immunotherapy has not been smooth. Early clinical trials using high-dose broad-spectrum immunosuppressants or non-specific anti-TNF-α monoclonal antibodies mostly ended in failure, and some even aggravated HF deterioration.⁶⁴ Three core underlying reasons are identified: Immune pathways have high redundancy and compensatory activation. Single blockade of one inflammatory factor triggers compensatory upregulation of other pathways, failing to achieve sustained inflammation inhibition. HF patients have strong heterogeneity. Inflammatory drivers vary completely across etiologies, phenotypes, and disease stages, so broad-spectrum anti-inflammatory therapy cannot match all patients’ immune characteristics. Inflammation has dual functions of injury and repair. Non-specific inhibition disrupts physiological repair after myocardial injury, further worsening cardiac function.

Currently, immune cell-targeted agents for inflammatory diseases form a multi-dimensional system, including monoclonal antibodies targeting cell surface markers, small-molecule activation inhibitors, adoptive cell therapy, and immunometabolism regulators. Among them, precise agents targeting specific pathogenic immune subsets can avoid the side effects of broad-spectrum immunosuppression while blocking inflammatory pathways, providing a safer direction for cardiovascular inflammatory disease treatment.⁶³

Small-Molecule Drug Therapy

Small-molecule drugs regulate immune cell polarization, activation, infiltration, and cytokine secretion by targeting cell surface receptors, intracellular signaling pathways, inflammatory mediators, and key metabolic molecules, thereby inhibiting myocardial inflammation, reducing fibrosis, and improving ventricular remodeling. They are the most widely studied intervention modality in preclinical and clinical research.

Anti-Inflammatory Targeted Drugs

A clinical trial of canakinumab (a fully human anti-IL-1β monoclonal antibody) in patients with prior myocardial infarction and elevated high-sensitivity C-reactive protein significantly reduced major adverse cardiovascular events, and substantially decreased HF hospitalization and HF-related mortality.⁶⁵

Among preclinical agents, the TLR4 inhibitor TAK-242 inhibits neutrophil NET formation in aged HF mice, reduces inflammatory markers, and alleviates myocardial injury and collagen deposition.⁶⁶ The PAD4 inhibitor GSK484 specifically blocks NET assembly, with efficacy comparable to DNase I.⁶⁷ The S100A9 inhibitor ABR-238901 targets myeloid S100A8/A9 activity, blocks inflammatory pathway activation, inhibits immune cell infiltration, and prevents the transition from compensatory hypertrophy to HF under pressure overload.⁶⁸

Multi-Target Synergy: Immunomodulatory Mechanisms of Conventional HF Drugs

Representative SGLT2 inhibitors include dapagliflozin and empagliflozin. Their clinical benefits involve multi-dimensional synergistic effects: hemodynamic improvement, renal protection, metabolic regulation, mitochondrial function optimization, and immunomodulation. They are core components of the standard “new quadruple therapy” for HF. Dapagliflozin directly inhibits macrophage inflammatory activation independently of SGLT2, thereby blocking abnormal fibroblast activation and attenuating post-infarction and pressure-overload HF remodeling. Notably, CCR2 antagonists completely abolish the cardioprotective effect of dapagliflozin, confirming that the CCR2 chemotactic axis is its core immunomodulatory target.⁶⁹

Empagliflozin inhibits neutrophil NET formation by downregulating cardiac HMGB1 expression, improving HFpEF diastolic dysfunction.⁴⁵ It also directly acts on mechanically stressed cardiac fibroblasts, reduces CCL2 secretion to decrease CCR2⁺ pro-inflammatory macrophage recruitment, and exerts independent anti-fibrotic effects.⁷⁰

Glucagon-like peptide-1 (GLP-1) receptor agonists are a research hotspot in metabolic cardiovascular diseases, with significant clinical benefits especially in obese phenotype HFpEF.⁷¹ These drugs exert cardioprotective effects by inhibiting excessive neutrophil activation and reducing systemic inflammatory load, while improving metabolic disorders and reducing body weight to alleviate HFpEF inflammatory drivers from the etiological level.⁷²

Novel non-steroidal mineralocorticoid receptor antagonists (MRAs) such as finerenone have been confirmed to significantly reduce HF onset and hospitalization risk. Their benefits include not only traditional aldosterone receptor blockade,⁷³ but also immunomodulatory pathways such as inhibiting pro-inflammatory macrophage polarization, reducing myocardial inflammatory infiltration, and alleviating fibrosis,⁷⁴ providing a clinically available option for HF anti-inflammatory therapy.

Precise Immunomodulation by Immunometabolic Small Molecules

Immunometabolic small molecules are exogenous or endogenous chemical substances that act as therapeutic interventions on specific intracellular targets to alter immune cell metabolic state. They regulate macrophage phenotypic transition via specific molecular pathways. For example, resolvin RvD2 (an endogenous inflammation-resolving mediator) inhibits pro-inflammatory macrophage polarization by activating the GPR18 receptor, alleviating pressure-overload myocardial inflammation and remodeling.⁷⁵ mTOR inhibitors target the macrophage mTOR pathway to regulate immune senescence, trained immunity, and polarization, inhibiting persistent low-grade inflammation in chronic HF.⁷⁶ OGT inhibitors promote macrophage transition from pro-inflammatory to anti-inflammatory phenotypes by downregulating IRF1 activity, improving HF myocardial dysfunction.⁷⁷

Biological Agent Therapy

Multiple breakthroughs have been made in immune biotherapy for cardiac injury and repair. In addition to anti-inflammatory cytokine monoclonal antibodies, agents targeting immune checkpoints and chemokine axes, as well as adoptive Treg and macrophage therapies, have shown good cardioprotective effects in preclinical studies. These strategies precisely reshape the cardiac immune microenvironment by regulating immune cell activation, differentiation, and recruitment, providing a new intervention path for post-infarction and chronic HF.⁷⁸

Anti-inflammatory cytokine monoclonal antibodies block the inflammatory cascade by specifically neutralizing circulating and local pro-inflammatory factors. IL12β (a shared subunit of IL-12/IL-23) is a key regulator of Th1/Th17 activation. Targeted IL12β blockade significantly inhibits immune cell infiltration in the heart and lungs, reduces pro-inflammatory factor secretion, and alleviates pressure-overload myocardial hypertrophy, fibrosis, and cardiac dysfunction.⁷⁹

Immune checkpoint molecules regulate immune cell activation thresholds and inflammatory balance; targeted agents modulate activation balance and avoid excessive immune damage. CD40 is highly expressed on CCR2⁺ macrophages. CD40 agonists initiate intercellular signaling between macrophages and effector memory CD8⁺ T cells, activating a positive inflammatory feedback loop mediated by IL-12b, TNF, and IFNγ; targeted CD40 blockade breaks this vicious cycle, inhibits excessive immune activation, and reduces the risk of myocarditis and secondary HF induced by immune checkpoint inhibitor therapy.⁸⁰

Notably, most biological agents are still in preclinical or early clinical stages, and their long-term safety, optimal dosage, and administration timing in HF remain unclear. Due to their high target specificity, efficacy is highly dependent on matching with patients’ immune phenotypes. Broad-spectrum administration without stratification may repeat the failure of early anti-TNF therapy, which is a core challenge for precision HF immunotherapy.

Other Novel Therapeutic Strategies

In addition to traditional small-molecule and biological agents, novel strategies based on immune cell metabolism regulation fit the multi-dimensional pathological characteristics of HF and represent a promising therapeutic direction.

Immune cell effector function is highly dependent on metabolic reprogramming: pro-inflammatory immune cells mostly rely on glycolysis, while anti-inflammatory and reparative cells mainly use oxidative phosphorylation and fatty acid oxidation. Targeting key molecules in glycolysis, fatty acid metabolism, and glutamine metabolism pathways precisely regulates immune cell polarization and effector function, inhibiting chronic low-grade inflammation without comprehensive immunosuppression, and improving myocardial remodeling and function.⁸¹

Targeting core immune cell metabolic molecules such as HIF-1α and AIF1 reshapes the balance of macrophage glycolysis and fatty acid oxidation, inhibits sustained pro-inflammatory activation, and breaks the cycle of persistent low-grade inflammation in chronic HF.⁸² Meanwhile, targeting myeloid fatty acid metabolism disorders downregulates Vcam1 expression, inhibits abnormal hematopoietic stem cell proliferation and activation, blocks the systemic inflammatory cascade, and significantly improves HFpEF diastolic dysfunction.⁸³

Under IL-10 deficiency, HF triggers such as pressure overload induce gut microbiota dysbiosis and intestinal barrier leakage, promoting intestinal inflammatory factors and endotoxins to enter the circulation, amplifying systemic low-grade inflammation, further promoting myocardial immune cell infiltration, and aggravating ventricular remodeling.⁸⁴ Targeted gut microbiota regulation and intestinal barrier repair effectively inhibit systemic inflammation transmission to the heart, serving as an important auxiliary target for comprehensive HF management.

Most novel strategies are still in basic research stages. Although cross-organ regulation and metabolic reprogramming have broad prospects, they have wide-ranging targets and difficult-to-control off-target effects, with a long path to clinical translation.

Summary and Outlook

In summary, persistent low-grade sterile inflammation mediated by immune cells has been confirmed as a core pathological driver of HF onset and progression. Cutting-edge technologies such as single-cell sequencing, spatial transcriptomics, and lineage tracing have overturned the traditional single understanding of the cardiac immune microenvironment. They have systematically revealed the high phenotypic, origin, and functional heterogeneity of major immune cell subsets (macrophages, T cells, neutrophils, etc), clarified their dual pro-inflammatory/anti-inflammatory roles and dynamic transitions across disease stages, confirmed significant HF phenotype and etiological heterogeneity in immune mechanisms, and dissected local immune-resident cell interaction networks and the immune-adipose-heart cross-organ regulatory axis, laying a solid theoretical foundation for HF immune-targeted therapy. Currently, breakthroughs have been made in anti-inflammatory biological agents, SGLT2 inhibitors, and other clinical drugs with immunomodulatory effects, and novel strategies such as small-molecule targeted drugs show good application prospects, bringing new hope for improving the treatment dilemma of HF, especially HFpEF.

However, many urgent problems remain in this field: Insufficient spatiotemporal dynamic understanding: Most studies focus on subset identification at single time points, lacking systematic analysis of immune cell phenotypic transition, spatial distribution, and functional evolution across different HF courses and etiologies, limiting the universality of therapeutic targets. Heterogeneous research evidence: Existing studies vary widely in disease models, intervention protocols, and detection technologies, with controversial conclusions. A standardized research system is needed to clarify the context-dependent roles of immune cells. Poor clinical translatability: Most basic studies use young single-etiology animal models, which cannot simulate the aging, multiple comorbidities, and complex medication background of clinical patients, and interspecies immune regulation differences exist. Insufficient therapeutic precision and safety: Most current immune-targeted drugs are broad-spectrum inhibitors that easily interfere with physiological immunity. Cell therapy faces functional exhaustion, and combination therapy timing and dosage lack standardization. Weak systemic regulatory mechanism research: Cross-system regulation (neuro-immune, gut-heart, cardiorenal interactions), as well as the roles of immunometabolism and epigenetics, have not been fully elucidated.

In the future, it is urgent to integrate single-cell multi-omics, spatial transcriptomics, and in vivo imaging to construct a high-resolution spatiotemporal cardiac immune atlas, and draw a panoramic mechanism map integrating immune cell interactions, dynamic inflammation evolution, and therapeutic targets, to precisely dissect immune signatures of HF with different etiologies and stages. Preclinical animal and organoid models closer to human pathological features should be established to optimize the clinical translation system of immunotherapy. Precise targeting technologies for specific immune cell subsets and functional states should be developed to avoid the risks of non-specific immunosuppression. Meanwhile, combining multi-dimensional targets such as immunometabolism and cross-organ interaction, individualized immune diagnosis and treatment schemes based on patient immune phenotypes should be established, ultimately promoting HF treatment to shift from traditional hemodynamic regulation to precise immunotherapy, and effectively improving the overall cure rate and long-term survival of HF patients.

Funding Statement

No specific funding was received for this work.

AI Use Declaration

The authors declare no use of generative artificial intelligence tools in the manuscript preparation process.

Abbreviations

ARNI, angiotensin receptor-neprilysin inhibitor; CMD, coronary microvascular dysfunction; cDCs, conventional dendritic cells; DAMPs, damage-associated molecular patterns; HF, heart failure; HFimpEF, heart failure with improved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IFN-γ, interferon-γ; LPS, lipopolysaccharide; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NETs, neutrophil extracellular traps; pDCs, plasmacytoid dendritic cells; SGLT2i, sodium-glucose cotransporter 2 inhibitor; TSLP, thymic stromal lymphopoietin; VEGFA, vascular endothelial growth factor A.

Data Sharing Statement

No new datasets were generated or analyzed for this review. No associated data are available for sharing.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no competing interests.