Key result
Anti-PD-1 therapy combined with tumor media amplifies cardiomyocyte ferroptosis ~5-fold, driving mitochondrial dysfunction and inflammation.
Why the study?
Immune checkpoint inhibitors targeting PD-1 frequently cause severe cardiotoxicity, but the underlying mechanisms involving tumor-host crosstalk and iron-dependent ferroptosis remain poorly defined.
Does the combination of tumor-conditioned media and anti-PD-1 antibody promote ferroptosis in primary neonatal murine ventricular cardiomyocytes, and can ferroptosis inhibitors reverse this effect?
Does the combination of tumor-conditioned media and anti-PD-1 antibody promote ferroptosis in primary neonatal murine ventricular cardiomyocytes, and can ferroptosis inhibitors reverse this effect?
Tumor-derived exosomal factors and PD-1 blockade synergistically drive ferroptotic cardiomyocyte death by impairing antioxidant defenses and amplifying inflammation, suggesting ferroptosis inhibition as a potential cardioprotective strategy during cancer immunotherapy.
May warrant monitoring for ferroptosis-related cardiotoxicity with anti-PD-1 in tumor contexts; leaves open whether pathway inhibition improves cardiac safety.
Immune checkpoint inhibitors (ICIs) targeting PD-1 frequently cause severe cardiotoxicity, yet the mechanisms involving tumor-host crosstalk remain poorly defined. Emerging evidence implicates ferroptosis, an iron-dependent regulated cell death, in cardiac injury during cancer immunotherapy. Primary neonatal murine ventricular cardiomyocytes (NMVCs) were exposed to lung cancer-derived tumor-conditioned media (TCM; tumor-conditioned media) enriched with exosomes, anti-PD-1 antibody, or both. Ferroptotic markers, mitochondrial bioenergetics, inflammatory signaling, and exosomal microRNA cargo were systematically evaluated using standardized biochemical assays, quantitative PCR, and targeted pharmacological rescue experiments. TCM primed cardiomyocytes for ferroptosis by downregulating the GPX4/SLC7A11/Nrf2 antioxidant axis, depleting glutathione, and elevating labile iron and lipid peroxidation. Anti-PD-1 treatment alone induced minimal oxidative stress but synergized with TCM to amplify ferroptosis > 4.7-fold, triggering profound mitochondrial depolarization and upregulating pro-ferroptotic enzymes ACSL4/LPCAT3. Tumor-derived exosomal miR-214-3p and miR-23a-3p directly suppressed GPX4 and Nrf2, mediating cellular vulnerability. The combined insult hyperactivated NF-κB and STING pathways in a mitochondria-dependent manner, markedly increasing pro-inflammatory cytokine secretion. Co-treatment with ferrostatin-1, deferoxamine, or Nrf2 activators effectively reversed ferroptotic markers and restored mitochondrial function. Tumor-derived exosomal factors and PD-1 blockade synergistically drive ferroptotic cardiomyocyte death by crippling antioxidant defenses and amplifying inflammatory signaling. Targeting ferroptosis or its upstream regulators presents a promising cardioprotective strategy for patients receiving cancer immunotherapy.
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Ma et al. (2026) studied Immune checkpoint inhibitor-induced cardiotoxicity. Lung cancer-derived tumor-conditioned media (TCM) plus anti-PD-1 antibody vs. TCM alone or anti-PD-1 antibody alone was evaluated on Cardiomyocyte ferroptosis, mitochondrial bioenergetics, and inflammatory signaling (> 4.7-fold amplification of ferroptosis). Anti-PD-1 treatment synergized with tumor-conditioned media to amplify cardiomyocyte ferroptosis > 4.7-fold, triggering mitochondrial depolarization and inflammation.
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