Adenosine 5′-triphosphate citrate lyase (ACLY) is a cytosolic enzyme that converts citrate into acetyl–coenzyme A for fatty acid and cholesterol biosynthesis. ACLY is up-regulated or activated in many cancers, and targeting ACLY by inhibitors holds promise as potential cancer therapy. However, the role of ACLY in cancer immunity regulation remains poorly understood. Here, we show that ACLY inhibition up-regulates PD-L1 immune checkpoint expression in cancer cells and induces T cell dysfunction to drive immunosuppression and compromise its antitumor effect in immunocompetent mice. Mechanistically, ACLY inhibition causes polyunsaturated fatty acid (PUFA) peroxidation and mitochondrial damage, which triggers mitochondrial DNA leakage to activate the cGAS-STING innate immune pathway. Pharmacological and genetic inhibition of ACLY overcomes cancer resistance to anti–PD-L1 therapy in a cGAS-dependent manner. Furthermore, dietary PUFA supplementation mirrors the enhanced efficacy of PD-L1 blockade by ACLY inhibition. These findings reveal an immunomodulatory role of ACLY and provide combinatorial strategies to overcome immunotherapy resistance in tumors.

The absence of contrast material washout in delayed phases was characteristic of most but not all intrahepatic cholangiocarcinomas (ICCs); thus, it was not adequate for the establishment of ICC dia... PurposeTo assess the accuracy of magnetic resonance (MR) imaging–based differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in a cohort of patients wit...

Background: Few data are available regarding the management and outcomes among patients with sarcomatoid hepatocellular carcinoma (HCC) due to its rarity.Methods: Patients diagnosed with sarcomatoid HCC from 2004 through 2015 were identified in the National Cancer Data Base. Overall survival (OS) was calculated among patients with sarcomatoid versus conventional HCC using a 1:3 propensity score matching based on sex, age, and American Joint Committee on Cancer (AJCC) stage of disease.Results: The final analytic cohort included 104 patients with sarcomatoid HCC and 312 patients with conventional HCC. Patients with sarcomatoid HCC more often had a larger median tumor size (8.5 cm vs 5.4 cm; P < .001) and poorly or undifferentiated tumors (52.9% vs 13.8%; P < .001) compared with patients who had conventional HCC. 5‐year OS was worse among patients with sarcomatoid versus conventional HCC (5.7% vs 30.1%; P < .001). Subgroup analysis demonstrated worse 5‐year OS among patients with sarcomatoid versus conventional HCC among patients treated with either curative‐intent or palliative therapies. Stage‐specific subgroup analysis indicated a worse OS among patients with AJCC stage I, stage II, or stage III sarcomatoid HCC. On multivariable analysis, uninsured status, advanced AJCC stage (stage III/stage IV), and histological sarcomatoid subtype were independently associated with worse outcomes (all P < .05).Conclusions: Sarcomatoid HCC is a very rare variant of HCC, which was associated with larger tumor size and worse tumor grade on presentation. On propensity score matched analyses that controlled for known confounding factors, patients with sarcomatoid HCC had a worse stage‐for‐stage long‐term survival compared with patients who had conventional HCC.