Elemene Augments the Effects of Anti‐PD‐1 Immunotherapy on Hepatocellular Carcinoma by Regulating the miR‐130a‐5p/SPP/MHC‐I Axis

Elemene increases SPP expression by competitively binding with miR‐130a‐5p to suppress SPP mRNA degradation. This led to more antigen/MHC‐I complexes being expressed on the cell surface, which consequently facilitated the recognition and killing of HCC cells by CTLs and enhancing the antitumor immune efficacy of anti‐PD‐1. Abstract Immune checkpoint inhibitors, particularly PD‐1 inhibitors, constitute the cornerstone of first‐line treatment for hepatocellular carcinoma (HCC). However, suboptimal overall response rates persist alongside dual challenges: immune‐related toxicities and immunosuppressive tumor microenvironment. Combination therapies represent a pivotal strategy to overcome these limitations. In recent years, traditional Chinese medicine has gained significant attention. Elemene, a small‐molecule compound derived from Curcuma wenyujin, has garnered attention for its immunomodulatory potential and demonstrates clinical efficacy in combination therapies. Nevertheless, its synergistic mechanisms with immunotherapy remain incompletely characterized. This study demonstrates for the first time that elemene modulates the miR‐130a‐5p/SPP/MHC‐I axis, resulting in an enhanced diversity and abundance of antigen/MHC‐I complexes on the surface of HCC cells. This mechanism promotes the recognition and elimination of HCC cells by cytotoxic T lymphocytes, thereby augmenting the antitumor immune efficacy of PD‐1. Moreover, the functional significance of the miR‐130a‐5p/SPP/MHC‐I axis in modulating the tumor immune microenvironment is systematically validated through in vitro and in vivo HCC models, as well as in clinical patient specimens. These findings underscore the potential of combining elemene with anti‐PD‐1 therapy as a safe and effective treatment strategy for HCC, offering significant translational promise for improving patient outcomes. Elemene increases SPP expression by competitively binding with miR-130a-5p to suppress SPP mRNA degradation. This led to more antigen/MHC-I complexes being expressed on the cell surface, which consequently facilitated the recognition and killing of HCC cells by CTLs and enhancing the antitumor immune efficacy of anti-PD-1. Abstract Immune checkpoint inhibitors, particularly PD-1 inhibitors, constitute the cornerstone of first-line treatment for hepatocellular carcinoma (HCC). However, suboptimal overall response rates persist alongside dual challenges: immune-related toxicities and immunosuppressive tumor microenvironment. Combination therapies represent a pivotal strategy to overcome these limitations. In recent years, traditional Chinese medicine has gained significant attention. Elemene, a small-molecule compound derived from Curcuma wenyujin, has garnered attention for its immunomodulatory potential and demonstrates clinical efficacy in combination therapies. Nevertheless, its synergistic mechanisms with immunotherapy remain incompletely characterized. This study demonstrates for the first time that elemene modulates the miR-130a-5p/SPP/MHC-I axis, resulting in an enhanced diversity and abundance of antigen/MHC-I complexes on the surface of HCC cells. This mechanism promotes the recognition and elimination of HCC cells by cytotoxic T lymphocytes, thereby augmenting the antitumor immune efficacy of PD-1. Moreover, the functional significance of the miR-130a-5p/SPP/MHC-I axis in modulating the tumor immune microenvironment is systematically validated through in vitro and in vivo HCC models, as well as in clinical patient specimens. These findings underscore the potential of combining elemene with anti-PD-1 therapy as a safe and effective treatment strategy for HCC, offering significant translational promise for improving patient outcomes. Advanced Science, EarlyView.