Metabolic Drivers of Bidirectional Heart–Cancer Crosstalk: From a Relatively Tumor-Restrictive Myocardium to Therapeutic Decoupling

Cardio-oncology has traditionally centered on treatment-related cardiotoxicity, yet cancer and cardiovascular disease influence one another before, during, and after therapy. This Review develops a direction-weighted staged framework for their metabolic interaction. We propose the healthy adult myocardium as a relatively tumor-restrictive environment in which metabolic reserve operates alongside mechanical, vascular, stromal, and immune constraints. Cancer can erode this reserve before overt cardiotoxicity through substrate redistribution, cachexia, mitochondrial stress, and circulating metabolites. Once metabolically injured, the heart can reshape immune, neurohumoral, metabolic, and vesicular signaling in ways that promote tumor progression; this heart-to-tumor direction constitutes reverse cardio-oncology within the broader bidirectional model. The proposed trajectory-from tumor-driven reserve loss to heart-derived reinforcement and subsequent stabilization or amplification-is common but not universal and may be reshaped by pre-existing cardiac disease or anticancer therapy. Evidence maturity differs across hubs: D-2-hydroxyglutarate provides the clearest source-defined tumor-to-heart proof of concept, whereas lactate handling and ferroptosis-related lipid-iron stress represent broader, testable, but less clinically resolved pathways. We translate these pathways into metabolic endotypes, provisional measurable criteria, and paired cardiac-oncologic endpoints to support therapeutic decoupling without compromising cancer control.