Ginsenoside Rh1 sensitizes gastric cancer to cuproptosis and represses immune evasion.

Cuproptosis is a novel type of cell death triggered by copper ions accumulation, which role is receiving increasing attention. Moreover, more evidence indicates that cuproptosis is closely related to tumor immunity. The objective of the present work was to investigate the anti-tumor effects and underlying mechanisms of Ginsenoside Rh1 (Rh1) on human gastric cancer (GC) through cuproptosis and tumor immune evasion. In vitro, Rh1 concentration-dependently repressed the proliferation and migration of GC cells. For the cuproptosis, Rh1 promoted the elesclomol-Cu (ES-Cu) or disulfiram-Cu induced proliferation inhibition. Besides, Rh1 damaged the subcellular structure and increased reactive oxygen species level in GC cells, which was also verified by the cuproptosis inhibitor Tetrathiomolybdate (TTM). For the GC immune evasion, Rh1 reduced the PD-L1 expression and accelerated the cytokines (IFN-γ, TNF-α), thereby repressing the immune evasion of GC cells. Furthermore, Rh1 could assist in enhancing the inhibitory effect of ES-Cu on GC immune evasion, while TTM reversed this effect. Mechanistically, ATP7A was verified to be targeted by Rh1, and Rh1 interacted with ATP7A to alter the copper-dependent immune evasion. In vivo, Rh1 was confirmed to repress the tumor growth and bolstered the infiltrated CD8 lymphocyte. Finally, this work verified that Ginsenoside Rh1 promoted the cuproptosis and repressed the immune evasion of GC cells. In short, Ginsenoside Rh1 attenuated the ATP7A to potentiate the copper accumulation and cuproptosis, thereby alleviating cuproptosis-related immune evasion.