Reverse cardio-oncology: neuroendocrine axis activation and cardiovascular-disease-derived factors synergistically remodel the tumor microenvironment.

Cardiovascular disease and cancer are increasingly recognized as biologically interconnected conditions with a bidirectional relationship. In addition to the well-established cardiotoxic effects of cancer therapies, accumulating epidemiological and experimental evidence suggests that cardiovascular disease may influence cancer initiation, progression, and metastasis, a concept referred to as reverse cardio-oncology. However, the mechanisms linking cardiovascular pathology to tumor microenvironment remodeling remain incompletely defined and are likely to involve multiple interacting systemic and local pathways. In this review, we summarize current evidence regarding the potential contribution of cardiovascular stress, neuroendocrine activation, metabolic dysregulation, impaired oxygen delivery, physical inactivity, and cardiovascular disease-derived secretory factors to tumor microenvironment remodeling. Particular attention is given to vascular endothelial growth factor, extracellular vesicles, reactive oxygen species, and inflammatory cytokines, which may act as interconnected mediators of angiogenesis, immune suppression, oxidative stress, and metastatic progression. We further discuss how these pathways may converge within a broader hierarchical and network-based framework, while emphasizing that much of the current mechanistic evidence remains derived from observational studies, animal models, and in vitro systems. Finally, we highlight therapeutic implications, including modulation of neuroendocrine and inflammatory signaling, and propose future directions involving human tissues, clinical samples, and heart-cancer-on-a-chip platforms. Overall, this review aims to provide a balanced synthesis of current knowledge and unresolved questions in reverse cardio-oncology, with the goal of supporting more integrated investigation of cardiovascular disease-cancer interactions.