Immunosuppressive CCR2+ cardiac macrophages mitigate myocardial injury in pancreatic cancer-associated cachexia
Cardiac wasting and injury are hallmarks of cancer cachexia, a metabolic syndrome characterized by reduced appetite and progressive loss of body weight in patients with cancer. However, the mechanisms underlying this cardiac pathology remain poorly understood. The heart is an immunologically complex organ, and cardiac myeloid cells have emerged as key regulators in various cardiomyopathies. Therefore, we investigated their contribution to cancer cachexia-induced cardiac wasting and injury. Using a murine model of pancreatic ductal adenocarcinoma (PDAC)-associated cachexia, we observed expansion of all cardiac macrophage subtypes and infiltration of neutrophils. Depletion of neutrophils had no impact on cardiac wasting and injury in tumor-bearing mice. In contrast, depletion of CCR2+ macrophages led to T cell expansion and activation within the heart, exacerbating myocardial inflammation and injury. These findings reveal a previously unrecognized protective immunosuppressive role for CCR2+ macrophages in PDAC cachexia. Finally, we identified reduced caloric intake as the major driver of cardiac wasting, highlighting a potential therapeutic avenue to preserve cardiac mass in patients with cancer cachexia.