Endoplasmic reticulum (ER) stress leads to hepatocellular carcinoma (HCC) progression. Small extracellular vesicles (sEV) play a crucial role in modulating the tumor microenvironment (TME) by influencing cellular communication and immune responses. However, it is unclear whether ER stress modulates the TME through sEVs. In the current study, we investigated the effects and underlying mechanisms of ER stress on the HCC TME. In vivo and in vitro experiments showed that overactivated ER stress was a salient attribute of the immunosuppressive HCC TME. This was caused by the ATF4-promoted release of small nucleolar RNA host gene 6 (SNHG6)-carrying sEVs, which attenuated T cell-mediated immune responses. Overall, SNHG6 modulated the immunosuppressive TME and aggravated ER stress. Meanwhile, targeting SNHG6 facilitated M1-like macrophage and CD8+ T-cell infiltration and decreased the proportion of M2-like macrophages. In addition, SNHG6 knockdown enhanced anti-PD1 immunotherapeutic efficacy. Moreover, in HCC patients, overexpression of SNHG6 was associated with a lack of response to anti-PD1 therapy and poor prognosis, whereas low SNHG6 expression was associated with improved therapeutic efficacy and prognoses. These data indicate that a correlation exists among ER stress, sEVs, immunosuppressive HCC TME, and immunotherapeutic efficacy. Hence, SNHG6-targeted therapy may represent an effective strategy for patients with HCC.

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