Hum Cell. 2026 Jul 9;39(7):102. doi: 10.1007/s13577-026-01415-y.
ABSTRACT
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, and their side effects, such as cardiotoxicity, have become critical complications. Herein, we explored the potential mechanism of ICIs-related cardiotoxicity. Healthy male C57BL/6 J mice were intraperitoneally injected with a PD-1/PD-L1 inhibitor (BMS-1) at a total dose of 60 mg/kg. BMS-1 treatment led to cardiac injury, with elevated cardiac enzyme levels, numbers of apoptotic cells, cardiomyocyte cross-sectional areas, and α-SMA expression. BMS-1-induced H9c2 cardiomyocyte injury was immune cell dependent. Compared with the control treatment, BMS-1 treatment did not significantly alter the T-cell composition in the peripheral blood or spleen. However, fluorescence imaging revealed increased numbers of CD3+ T cells, F4/80+ macrophages, and Ly6G+ neutrophils in the hearts of BMS-1-treated mice. In addition, BMS-1 treatment also increased PD-L1 expression and activated inflammatory pathways, including AKT, p38 MAPK, mTOR, and STAT3. Interestingly, the expression of the inflammatory genes Il1b, Il17a, and Ifng; the T-cell activation genes Nkg7 and Cst7; the exhaustion genes Klrg1 and Tigit; and the transcription factors Tbx21 and Rora were markedly elevated in the thymus, but their expression was unchanged in the peripheral blood and spleen. Furthermore, electron microscopy revealed mitochondrial swelling and lipid droplets in the hearts of BMS-1-treated mice. Compared with those in control hearts, the levels of the lipid metabolism proteins p-ACC, p-ACLY, FASN, and Lipin 1 were consistently upregulated in the hearts of BMS-1-treated mice. Taken together, these findings suggested that the PD-1/PD-L1 inhibitor BMS-1 induced inflammation in the heart. Alterations in cardiac lipid metabolism might be correlated with ICIs-related cardiotoxicity.
PMID:42423862 | DOI:10.1007/s13577-026-01415-y