Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression. [Display omitted] •NBR1 loss reverts the HCC tumor-promoting function of p62-deficient HSCs•NBR1 regulates STING levels via lysosomal degradation, independent of autophagy•NBR1 and p62 oppositely modulate the IFN pathway by regulating STING ubiquitination•NBR1 loss activates HSC’s IFN, enhancing CD8+ T cells and anti-tumor immunity in HCC Nishimura et al. demonstrate that NBR1 is a synthetic vulnerability of p62 deficiency in HSCs by opposingly regulating the STING-interferon cascade. NBR1 ablation results in the accumulation of STING and its ability to activate IFN signaling, antagonizing the effect of p62 deficiency, which increases anti-tumor immunity in HCC.