Background and aims Human solid tumors such as hepatocellular carcinomas (HCC) establish a complex immunosuppressive tumor microenvironment (TME) that undermines the efficacy of existing immunotherapies such as chimeric antigen receptor T (CAR T) cell therapy. To advance immunotherapy for HCC, it is crucial to delineate the molecular mechanisms that drive TME formation and immune evasion. Methods We integrated bulk and single-cell RNA sequencing analysis to assess immune regulation and conduct pathway enrichment analyses. The oncogenic roles of SKIV2L were revealed by comparing the proliferation and tumorigenesis of HCC with or without SKIV2L knockdown. SKIV2L-driven mechanisms were investigated using RNA sequencing, RNA immunoprecipitation sequencing, immunoprecipitation-mass spectrometry, and proximity ligation assay. Functional studies of SKIV2L in arginine metabolism and anti-tumor immunity were performed using flow cytometry and tumor-T cell co-culture assays. Results SKIV2L was overexpressed in HCC, and its expression levels negatively correlated with patient prognosis and tumor immune cell infiltration. Depletion of SKIV2L disrupted the immunosuppressive landscape of HCC, enhanced systemic antitumor immunity, and significantly augmented the efficacy of CAR T cell therapy. Mechanistically, SKIV2L promoted arginine metabolism in HCC by recruiting GNL3 to stabilize mRNAs encoding key regulators of arginine uptake and metabolism, including the arginine transporter SLC7A1 and the arginine-catabolizing enzyme ARG2. This SKIV2L–arginine axis fostered an immunosuppressive TME and impaired T-cell function. Furthermore, SKIV2L was identified as a direct transcriptional target of c-Myc, positioning SKIV2L as a druggable mediator of c-Myc-driven oncogenesis. Conclusions Our findings identify a novel c-Myc–SKIV2L–arginine metabolism axis that drives HCC progression and immune evasion. Targeting SKIV2L reprograms TME and reinvigorates antitumor immunity, providing a promising therapeutic strategy to overcome resistance to immunotherapy such as CAR T cell therapy in HCC.
Zhu et al. (Wed,) studied this question.