Anthracycline Cardiotoxicity as Multicellular Network Failure: Cardiac Niche Reprogramming and Pathological Cell-Cell...

Anthracyclines are essential anticancer agents, yet a cardiomyocyte-centered model incompletely explains why cardiac injury can be delayed, progressive, and poorly captured by resting ejection fraction. We frame anthracycline cardiotoxicity as a multicellular network failure within the cardiac niche: the spatially organized interactions among cardiomyocytes, fibroblasts, endothelial and immune cells, extracellular matrix, and circulating signals. Cardiomyocyte stress initiates injury, whereas pathological communication may propagate it. We distinguish a fibroblast-CD8⁺ T-cell adhesion circuit, supported by loss-of-function evidence in mice and correlative human data, from an emerging therapy-conditioned tumor-heart extracellular vesicle axis supported mainly by breast cancer models. These pathways may converge on fibrotic stiffness, microvascular dysfunction, and electrical uncoupling; however, direct cross-circuit interaction and drug-independent sufficiency remain unproven. We integrate established clinical risk modifiers with this framework, specify causal criteria, and propose spatial multiomics, living myocardial slices, tumor-bearing systems, and longitudinal phenotyping to test circuit persistence. This evidence-calibrated model shifts the goal from cataloging cell-intrinsic pathways to identifying mechanism-resolved biomarkers and therapeutically targetable communication nodes while preserving antitumor efficacy.