Melanoma is the most lethal type of
skin cancer, originating from the malignant transformation of melanocyte. While the development of targeted
therapy and
immunotherapy has gained revolutionary advances in potentiating the
therapeutic effect, the prognosis of patients with
melanoma is still suboptimal. During
tumor progression,
melanoma frequently encounters stress from both endogenous and exogenous sources in tumor microenvironment. SIRT7 is a nuclear-localized deacetylase of which the activity is highly dependent on intracellular
nicotinamide adenine dinucleotide (
NAD+), with versatile biological functions in maintaining cell homeostasis. Nevertheless, whether SIRT7 regulates
tumor cell biology and
tumor immunology in
melanoma under stressful tumor microenvironment remains elusive. Herein, we reported that SIRT7 orchestrates
melanoma progression by simultaneously promoting
tumor cell survival and immune evasion via the activation of unfolded protein response. We first identified that SIRT7 expression was the most significantly increased one in
sirtuins family upon stress. Then, we proved that the deficiency of SIRT7 potentiated
tumor cell death under stress in vitro and suppressed
melanoma growth in vivo. Mechanistically, SIRT7 selectively activated the IRE1α-XBP1 axis to potentiate the pro-survival ERK signal pathway and the secretion of
tumor-promoting
cytokines. SIRT7 directly de-acetylated SMAD4 to antagonize the TGF-β-SMAD4 signal, which relieved the transcriptional repression on IRE1α and induced the activation of the IRE1α-XBP1 axis. Moreover, SIRT7 up-regulation eradicated anti-
tumor immunity by promoting PD-L1 expression via the IRE1α-XBP1 axis. Additionally, the synergized
therapeutic effect of SIRT7 suppression and anti-PD-1
immune checkpoint blockade was also investigated. Taken together, SIRT7 can be employed as a promising target to restrain
tumor growth and increase the effect of
melanoma immunotherapy.