The up‐regulation of PD‐L1 during boningmycin‐induced senescence in human cancer cells depends on the activation of the JAK/STAT signaling pathway mediated by SASP

Abstract

AbstractTherapy‐induced senescence can regulate both the innate and adaptive immune systems, thereby affecting therapeutic efficacy. Bleomycin is a major component of combined chemotherapy regimens, utilized for the treatment of multiple tumors, whereas pulmonary toxicity severely restricts its clinical benefits. As a member of the bleomycin family, boningmycin (BON) exhibits potent anticancer activity with minimal pulmonary toxicity, making it a potential alternative to bleomycin. Low concentrations of BON can induce senescence, but the impact of BON‐induced senescence on anticancer immunity remains unclear. This study investigates the effects of BON‐induced senescence on PD‐L1 expression and the underlying mechanisms in human cancer cells. Firstly, the elevation of PD‐L1 protein during BON‐induced senescence was confirmed by a senescence β‐galactosidase staining assay, detection of the senescence‐associated secretory phenotype (SASP), western blot and flow cytometry in human lung cancer NCI‐H460 cells and breast cancer MDA‐MB‐231 cells. Subsequently, it was shown that the increase in PD‐L1 protein is mediated by SASP, as evidenced by the use of conditional media, knockdown of cyclic GMP‐AMP synthase and inhibition of stimulator of interferon genes. Ultimately, it was demonstrated that SASP‐mediated PD‐L1 up‐regulation is dependent on the activation of the JAK/STAT pathway through the use of specific inhibitors and siRNAs. These findings clarify the impact of BON‐induced senescence on PD‐L1 expression and may contribute to the optimization of the therapeutic efficacy of bleomycin‐related compounds and the clinical transformation of BON.