Abstract
<div>Abstract<p>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. <i>In vivo</i> and <i>in vitro</i> experiments showed that overactivated ER stress was a salient attribute of the immunosuppressive HCC TME. This was caused by the <i>ATF4</i>-promoted release of small nucleolar RNA host gene 6 (<i>SNHG6</i>)-carrying sEVs, which attenuated T cell-mediated immune responses. Overall, <i>SNHG6 </i>modulated the immunosuppressive TME and aggravated ER stress. Meanwhile, targeting <i>SNHG6 </i>facilitated M1-like macrophage and CD8<sup>+</sup> T-cell infiltration and decreased the proportion of M2-like macrophages. In addition, <i>SNHG6 </i>knockdown enhanced anti-PD1 immunotherapeutic efficacy. Moreover, in HCC patients, overexpression of <i>SNHG6</i> was associated with a lack of response to anti-PD1 therapy and poor prognosis, whereas low <i>SNHG6</i> 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, <i>SNHG6</i>-targeted therapy may represent an effective strategy for patients with HCC.</p></div>
Published Version
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