Immune–fibroblast ligand–receptor axes in post-infarction cardiac remodeling: convergent and divergent mechanisms compared with cancer-associated fibroblasts

Myocardial infarction-triggered cardiac fibrosis is a cardinal feature of maladaptive ventricular remodeling and a principal contributor to heart failure pathogenesis. Enabled by single-cell RNA sequencing and spatial transcriptomics, accumulating evidence demonstrates that post-infarction fibrosis represents an actively coordinated biological program rather than a passive wound-healing event, which is governed by ligand-receptor-mediated crosstalk between immune cells and cardiac fibroblasts. Pioneering work has established monocyte-derived macrophages as a predominant cellular source of pro-inflammatory interleukin-1β; upon binding its cognate receptor on fibroblasts, this cytokine instigates the generation of pro-fibrotic fibroblast subsets within spatially segregated niches of the infarcted myocardium. Multiple additional ligand-receptor modules, encompassing osteopontin-CD44/integrin, transforming growth factor-β, platelet-derived growth factor, as well as growth arrest-specific protein 6-MER tyrosine kinase, further fine-tune fibroblast activation trajectories in a spatiotemporally-restricted fashion. Intriguingly, a substantial fraction of these ligand-receptor interactions are conserved in cancer-associated fibroblast biology, wherein osteopontin-producing macrophages and activated fibroblasts collaboratively build pro-tumor stromal microenvironments. We consolidate recent multi-omic findings regarding immune-fibroblast ligand-receptor communication during post-infarction cardiac remodeling, highlight mechanistic analogies to cancer-associated fibroblast activation, and discuss therapeutic prospects arising from targeting these conserved signaling nodes across cardiac and neoplastic diseases.