DNA-damaging chemotherapy reshapes cardiac-resident macrophage composition and function.

Summary

In murine models, DNA-damaging chemotherapies deplete embryonic-derived cardiac-resident macrophages via p53-driven necroptosis/apoptosis. Monocyte-derived resident-like macrophages reconstitute the niche, exhibit distinct transcriptional profiles, and protect against subsequent hypertensive and ischemic injury through type I interferon-dependent mechanisms.

Key Findings

• DNA-damaging agents activate p53 signaling in cardiac-resident macrophages, causing necroptosis and apoptosis with selective depletion.
• Monocytes progressively reconstitute the resident macrophage compartment with a transcriptionally distinct, resident-like phenotype.
• Monocyte-derived resident-like macrophages suppress inflammation and attenuate adverse remodeling after hypertensive and ischemic injury via type I interferon-dependent mechanisms.

Clinical Implications

Findings suggest new avenues for cardio-oncology: monitoring immune remodeling after chemotherapy, and therapeutically modulating monocyte/macrophage programs or type I interferon signaling to mitigate cardiac injury risk.

Limitations

• Preclinical murine models; human validation of immune remodeling and clinical translation are pending
• Detailed temporal dynamics and dose-response across diverse chemotherapies require further study

Future Directions

Validate immune remodeling in patients receiving DNA-damaging chemotherapy; test macrophage-targeted or type I interferon–modulating strategies to prevent chemotherapy-related cardiac injury.