Itaconate is a metabolite catalyzed by cis- aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent chronic liver disorder with complex pathogenesis and limited therapeutic options. Here, we identify the solute carrier SLC13A3 as a critical regulator of MASLD progression. In a mouse model fed a high-fat, high-cholesterol, and high-fructose (HFHCHF) diet, hepatic SLC13A3 expression was significantly upregulated and positively correlated with disease severity. Liver-specific overexpression of Slc13a3 exacerbated hepatic steatosis, lipid accumulation, and metabolic dysfunction, whereas Slc13a3 knockdown attenuated these pathological phenotypes. Targeted metabolomic analysis revealed that SLC13A3 modulates hepatic NAD + levels, thereby influencing the expression of key lipid metabolism genes, including SREBF1 , CD36 , PPARγ , and SCD1 . These findings highlight a previously unrecognized role of SLC13A3 in MASLD pathogenesis and suggest its potential as a therapeutic target.
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