Targeting the heart-immune axis after myocardial infarction: from inflammation to immunomodulation

Myocardial infarction (MI) triggers a systemic immune response involving bidirectional crosstalk between the injured heart and remote immune organs. However, the dynamic, multi-organ nature of this "heart-immune axis" remains poorly defined. By targeting specific aspects of the immune response, particularly the modulation of macrophage polarization and the attenuation of excessive inflammation, this strategy holds therapeutic potential for preserving cardiac function and enhancing long-term patient outcomes, thereby opening a new frontier in cardiovascular therapeutics. In this review, we propose a novel framework that divides post-MI immune response into three interconnected phases: inflammation, resolution, and remodeling. Within each phase, we delineate the bidirectional crosstalk mechanisms between the injured heart and immune organs via cytokine networks and hematopoietic progenitor mobilization. We then critically evaluate emerging immunomodulatory strategies, ranging from targeting CCR2/CCL2 axis, promoting regulatory T cells, with emphasis on their mechanistic rationale, clinical trial progress, and major translational gaps. Unlike conventional anti-inflammatory approaches that suppress broad immune activity, axis-targeted immunomodulation aims to preserve or restore protective cardiac repair. This review provides a phase-specific, multi-organ, and therapeutically actionable roadmap of the heart-immune axis, offering new perspectives for next-generation MI therapies.